Bone implant and systems and coatings for the controllable release of antimicrobial metal ions

ABSTRACT

Antimicrobial metal ion coatings and implants including them. In particular, described herein are coatings including an anodic metal (e.g., silver and/or zinc and/or copper) that is co-deposited with a cathodic metal (e.g., palladium, platinum, gold, molybdenum, titanium, iridium, osmium, rhodium, manganese, niobium or rhenium) on a substrate so that the anodic metal is galvanically released as antimicrobial ions when the apparatus is exposed to a bodily fluid. The anodic metal may be at least about 25 percent by volume of the coating, resulting in a network of anodic metal with less than 20% of the anodic metal in the coating fully encapsulated by cathodic metal. The implant may be configured as an implant such as a bone-screw or intramedullary rod-like body configured to receive a treatment cartridge having a coating as described.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims priority as a continuation-in-part toU.S. patent application Ser. No. 14/833,569, filed on Aug. 24, 2015, andtitled “COATINGS FOR THE CONTROLLABLE RELEASE OF ANTIMICROBIAL METALIONS,” now U.S. Pat. No. 9,821,094, which is a continuation-in-part ofU.S. patent application Ser. No. 14/679,893, filed on Apr. 6, 2015,titled “COATINGS FOR THE CONTROLLABLE RELEASE OF ANTIMICROBIAL METALIONS,” now U.S. Pat. No. 9,114,197, which is a continuation-in-part ofU.S. patent application Ser. No. 14/569,545, filed on Dec. 12, 2014,titled “BIOABSORBABLE SUBSTRATES AND SYSTEMS THAT CONTROLLABLY RELEASEANTIMICROBIAL METAL IONS,” now U.S. Pat. No. 8,999,367, which is acontinuation of U.S. patent application Ser. No. 14/302,352, filed onJun. 11, 2014, titled “BIOABSORBABLE SUBSTRATES AND SYSTEMS THATCONTROLLABLY RELEASE ANTIMICROBIAL METAL IONS,” now U.S. Pat. No.8,927,004. Ser. No. 14/833,569 also claims priority to U.S. ProvisionalPatent Application No. 62/059,714, filed on Oct. 3, 2014 and titled“COATINGS FOR THE CONTROLLABLE RELEASE OF ANTIMICROBIAL METAL IONS.”Each of these patents and patent applications is herein incorporated byreference in its entirety.

This patent application also claims priority as a continuation-in-partto U.S. patent application Ser. No. 14/801,732, filed on Jul. 16, 2015,titled “BONE IMPLANT AND SYSTEMS THAT CONTROLLABLY RELEASES SILVER,” nowU.S. Patent Application Publication No. 2017-0014607-A9, which is acontinuation of U.S. patent application Ser. No. 13/748,546, filed onJan. 23, 2013, titled “BONE IMPLANT AND SYSTEMS THAT CONTROLLABLYRELEASES SILVER,” now U.S. Pat. No. 9,108,051, which is a divisional ofU.S. patent application Ser. No. 13/231,219, filed on Sep. 13, 2011,titled “BONE IMPLANT AND SYSTEMS THAT CONTROLLABLY RELEASES SILVER,” nowU.S. Pat. No. 8,771,323, which claims priority to the following U.S.Provisional Patent Applications: U.S. Provisional Patent Application No.61/413,230, filed on Nov. 12, 2010, and titled “SILVER ELUTING BONEIMPLANTS AND METHODS OF USE;” U.S. Provisional Patent Application No.61/438,162, filed on Jan. 31, 2011, and titled “BONE SUPPORTING IMPLANTSWITH ANTIBACTERIAL PROPERTIES;” U.S. Provisional Patent Application No.61/447,393, filed on Feb. 28, 2011, and titled “INTRAMEDULLARY(INTRAOSSEAL) ROD, NAIL OR CATHETER WITH GALVANICALLY PRODUCEDANTIBACTERIAL PROPERTIES;” U.S. Provisional Patent Application No.61/465,350, filed on Mar. 18, 2011, and titled “ANTIMICROBIAL IMPLANT TOPROVIDE MECHANICAL SUPPORT FOR A BORE THAT UTILIZES A GALVANIC POTENTIALBETWEEN TWO OR MORE METALS TO CREATE IONS THAT ARE GERMICIDAL AND/ORANTIFUNGAL;” U.S. Provisional Patent Application No. 61/516,388, filedon Apr. 4, 2011, and titled “GALVANIC ANTIMICROBIAL BONE SCREW FOR THETREATMENT OF DISEASED, FRACTURE OR MISALIGNED BONE AND TO PROMOTE BONEGROWTH AND REGENERATION,” each of which is incorporated by reference inits entirety.

U.S. patent application Ser. No. 14/801,732 is also acontinuation-in-part of U.S. patent application Ser. No. 13/527,389,filed on Jun. 19, 2012, titled “BONE IMPLANTS FOR THE TREATMENT OFINFECTION,” now U.S. Pat. No. 9,248,254, which is a continuation of U.S.patent application Ser. No. 12/870,082, filed Aug. 27, 2010, titled“BONE IMPLANTS FOR THE TREATMENT OF INFECTION,” now U.S. Pat. No.8,221,396, which claims priority to the following U.S. ProvisionalPatent applications: U.S. Provisional Patent Application No. 61/237,506,filed on Aug. 27, 2009, titled “SILVER ELLUTING BONE IMPLANTS ANDMETHODS OF USE;” U.S. Provisional Patent Application No. 61/340,587,filed on Mar. 19, 2010, titled “ANTIMICROBIAL ION ELUTING IMPLANTABLEDEVICE;” and U.S. Provisional Patent Application No. 61/359,549, filedon Jun. 29, 2010, titled “SILVER ELUTING BONE IMPLANTS AND METHODS OFUSE,” each of which is incorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

Described herein are substrates having antimicrobial metal ion coatings.In particular, described herein are substrates that are coated with ananodic metal (e.g., silver and/or zinc and/or copper) that isco-deposited with a cathodic metal (e.g., palladium, platinum, gold,molybdenum, titanium, iridium, osmium, niobium, rhodium, manganese, orrhenium) on the substrate to form a continuous path of interconnectedveins of anodic metal within the matrix of cathodic metal or acontinuous path of interconnected veins of cathodic metal within thematrix of anodic metal, wherein the continuous path extends from anouter surface of the coating to the substrate. Thus, the antimicrobialanodic metal (e.g., silver, zinc, copper) may be galvanically releasedas antimicrobial ions when the coated substrates is contacted by aconductive fluid environment, including when inserted into a subject'sbody.

BACKGROUND

Antimicrobial or antibiotic agents are widely used to treat as well asto prevent infection. In particular, silver is known to be antimicrobialand has been used (primarily as a coating) in various medical deviceswith limited success. Both active (e.g., by application of electricalcurrent) and passive (e.g., galvanic) release of silver ions have beenproposed for use in the treatment and prevention of infection. However,the use of silver-releasing implants have been limited because of thedifficulty in controlling and distributing the release of silver ions aswell as the difficulty in maintaining a therapeutically relevantconcentration of silver ions in an appropriate body region. Zinc sharesmany of the same antimicrobial properties of silver, but has been lesscommonly used, and thus even less is known about how to control theamount and distribution of the release of silver ions to treat and/orprevent infection.

It would be highly beneficial to use an antimicrobial agent such assilver and/or zinc as part of an implant, including a bioabsorbableimplant, in part because the risk of acquiring infections frombioabsorbable materials in medical devices is very high. Many medicalapplications exist for bioabsorbable materials including: wound closure(e.g., sutures, staples, adhesives), tissue repair (e.g., meshes, suchas for hernia repair), prosthetic devices (e.g., internal bone fixationdevices, etc.), tissue engineering (e.g., engineered blood vessels,skin, bone, cartilage, liver, etc.) and controlled drug delivery systems(such as microcapsules and ion-exchange resins). The use ofbioabsorbable materials in medical applications such as these may reducetissue or cellular irritation and the induction of an inflammatoryresponse.

Bioabsorbable materials for medical applications are well known. Forexample, synthetic bioabsorbable polymers may includepolyesters/polylactones such as polymers of polyglycolic acid,glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc.,polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, andcopolymers of these and related polymers or monomers, as well asnaturally derived polymers such as albumin, fibrin, collagen, elastin,chitosan, alginates, hyaluronic acid; and biosynthetic polyesters (e.g.,3-hydroxybutyrate polymers). However, like other biomaterials,bioabsorbable materials are also subjected to bacterial contaminationand can be a source of infections which are difficult to control. Thoseinfections quite often require their removal and costly antimicrobialtreatments.

Efforts to render bioabsorbable materials more infection resistantgenerally have focused on impregnating the materials with antibiotics orsalts such as silver salts, and have provided only limited andinstantaneous antimicrobial activity. It is desirable to have anantimicrobial effect which is sustained over time, such that theantimicrobial effect can be prolonged for the time that thebioabsorbable material is in place. This can range from hours or days,to weeks or even years.

Further, although antimicrobial/antibacterial metal coatings on medicaldevices have been suggested, metal coatings (such as silver or coppercoatings) have not been characterized or optimized. In suchapplications, it is important that the metal coatings do not shed orleave behind large metal particulates in the body, which may induceunwanted immune responses and/or toxic effects. Further, it is essentialthat the release of the antimicrobial agent (metal) be metered over thelifetime of the implant.

For example, U.S. Pat. No. 8,309,216 describes substrates includingdegradable polymers that include an electron donor layer (such assilver, copper or zinc) onto which particles of palladium and platinum,plus one other secondary metal (chosen from gold, ruthenium, rhodium,osmium, iridium, manganese or platinum) are deposited onto. Althoughsuch materials are described for anti-microbial implants (e.g.,pacemakers, etc.), the separate layers formed by this method would beproblematic for antimicrobial coatings in which the undercoating ofsilver, copper or zinc were being released, potentially undermining theplatinum and secondary metal.

Similarly, U.S. Pat. No. 6,719,987 describes bioabsorbable materialshaving an antimicrobial metal (e.g., silver) coating that can be usedfor an implant. The silver coating is for release of particles(including ions) and must be in a crystalline form characterized bysufficient atomic disorder. In this example, the silver is alsodeposited in one or more layers. U.S. Pat. No. 6,080,490 also describesmedical devices with antimicrobial surfaces that are formed by layers ofmetals (e.g., silver and platinum) to release ions; layers are etched toexpose regions for release. The outer layer is always Palladium (and oneother metal), beneath which is the silver.

Thus, it would be highly desirable to provide devices, systems andmethods for the controlled release (particularly the controlled galvanicrelease) of a high level of silver, zinc or silver and zinc ions from abioabsorbable material into the tissue for a sufficient period of timeto treat or prevent infection.

Known systems and devices, including those described above, that haveattempted to use ions (e.g., silver and/or zinc) on bioabsorbablematerials to treat infection have suffered from problems such as:insufficient amounts of ions released (e.g., ion concentration was toolow to be effective); insufficient time for treatment (e.g., the levelsof ions in the body or body region were not sustained for a long enoughperiod of time); and insufficient region or volume of tissue in whichthe ion concentration was elevated (e.g., the therapeutic region was toosmall or limited, such as just on the surface of a device). Further, theuse of galvanic release has generally been avoided or limited because itmay effectively corrode the metals involved, and such corrosion isgenerally considered an undesirable process, particularly in a medicaldevice.

For example, Osteomyelitis is an infection of a bone by a microorganismsuch as bacteria or fungi. Diabetes, joint replacement, trauma, andinjected drug use can lead to osteomyelitis. As people live longer,incidences of osteomyelitis are expected to increase. To complicatematters, an infection, such as following joint replacement surgery, canoccur long after the incision has been closed. An infection buried in abone can be difficult to detect; it is not visible to the eye and takinga culture sample is difficult and painful. Once diagnosed, antibioticscan eliminate many infections. Unfortunately, microorganisms aredeveloping resistances rendering existing antibiotics useless. Reportsof patients infected with microorganisms resistant to regular and “lastresort” antibiotics are increasing in number. For these patients, thereare few or no effective options. The problem is expected to become worseas microorganisms exchange genetic material and more species becomeresistant to antibiotics. Prophylactic use of antibiotics, althoughcommonly done, is discouraged because it may increase antibioticresistance. Infection with methicillin resistant Staphylococcus aureus(MRSA) is a significant health problem that is expected to worsen.Additionally, microorganisms on the surface of an artificial joint orother implanted device can cooperate to create an impervious layer,called a biofilm. A biofilm may form a mechanical barrier to anantibiotic.

Silver is known to be antimicrobial and has been used (primarily as acoating) in various medical devices with limited success. Both active(e.g., by application of electrical current) and passive (e.g.,galvanic) release of silver ions have been proposed for use in thetreatment and prevention of infection. However, the use ofsilver-releasing implants have been limited because of the difficulty incontrolling and distributing the release of silver ions as well as thedifficulty in maintaining a therapeutically relevant concentration ofsilver ions in an appropriate body region. Zinc shares many of the sameantimicrobial properties of silver, but have been less commonly used,and thus even less is known about how to control the amount anddistribution of the release of silver ions to treat and/or preventinfection.

Thus, it would be highly desirable to provide device systems and methodsfor the controlled release (particularly the controlled galvanicrelease) of a high level of silver, zinc or silver and zinc ions intothe tissue for a sufficient period of time to treat or preventinfection.

Specifically, known systems and devices that have attempted to use ions(e.g., silver and/or zinc) to treat infection have suffered fromproblems such as: insufficient amounts of ions released (e.g., ionconcentration was too low to be effective); insufficient time fortreatment (e.g., the levels of ions in the body or body region were notsustained for a long enough period of time); and insufficient region orvolume of tissue in which the ion concentration was elevated (e.g., thetherapeutic region was too small or limited, such as just on the surfaceof a device). Further, the use of galvanic release has generally beenavoided or limited because it may effectively corrode the metalsinvolved, and such corrosion is generally considered an undesirableprocess, particularly in a medical device.

In general, controlled release of silver and/or zinc ions would bebeneficial. Control of the release of ions may allow the treatment ofthe patient to be regulated by turning the release on/off. In general,silver coated devices do not typically allow for the controlled releaseof ions. Silver coatings or impregnations do not typically allowcontrolled release, because they are always “on” (e.g., always releasingsilver) to some degree. Zinc coatings on traditional implants may sufferfrom the same problem. Since release depends on the ionic concentrationof body fluids, the actual release (and therefore concentration) of ionsmay be difficult to predict and control.

There is a need for antimicrobial coatings for substrates generally.Antimicrobial coatings may be useful for any surface that will beexposed to a conductive fluid, including blood, sweat, lymph, etc.,whether implanted or not. For example, there is a particular need forantimicrobial coatings for bioabsorbable materials, which can create aneffective and sustainable antimicrobial effect, which do not interferewith the bioabsorption of the bioabsorbable material, and which do notshed or leave behind large metal particulates in the body as thebioabsorbable material disappears.

Therapeutically, the level of silver and/or zinc ions released into abody is important, because it may determine how effective theantimicrobial ions are for treating or preventing infection. Asdescribed in greater detail below, the amount or ions releasedgalvanically may depend on a number of factors which have not previouslybeen well controlled. For example, galvanic release may be related tothe ratio of the anode to the cathode (and thus, the driving force) aswell as the level of oxygen available; given the galvanic reaction, thelevel of oxygen may be particularly important for at the cathode.Insufficient oxygen at the cathode may be rate-limiting for galvanicrelease.

For example, with respect to silver, it has been reported that aconcentration of 1 mg/liter of silver ions can kill common bacteria in asolution. Silver ions may be generated a galvanic system with silver asthe anode and platinum or other noble metal as the cathode. However oneof the challenges in designing a galvanic system for creation of silverion in the body that has not been adequately addressed is theappropriate ratios of the areas of the electrodes (e.g., anode tocathode areas) in order to create the germicidal level of free silverions. One challenge in designing a galvanic system is addressing theparasitic loss of current due to formation of silver chloride viareaction:AgCl+e→Ag+Cl(−)Eo=0.222 volts

We herein propose that it may be beneficial to have an area of thecathode under common biological condition that is at least larger than8% of the silver area to sustain the germicidal level of silver ions.For the purpose of this discussion, the following assumptions have beenmade: for a concentration of: [H+]=10^(−7) moles/liter; [OH−]=10^(−7)moles/liter; [O2]=5*10^(−3) moles/liter in the capillary; [Cl−]=0.1moles/liter. The values of the following were also assumed (as constantsor reasonable approximations): Faraday's constant, F=96000coulombs/mole; diffusivity of oxygen=0.000234 cm2/sec; diffusivity ofAg+=10^(−6) cm2/sec; diffusivity of Cl−=10^(−6) cm2/sec; R, Gasconstant=8.314 J K⁻¹ mol⁻¹; T, temp. K; Mw of silver=108 grams/mol;germicidal concentration of silver=10^(−5) mol/liter.

At equilibrium, for a galvanic cell it is acceptable to assume that thetwo electrodes are at the same potential. Using the Nernst equation, theequilibrium concentration of oxygen when the silver ion is at thegermicidal level may be calculated:E=Eo−(RT/nF)ln [(Activity of products)/(activity of reactants)]E=Eo−(0.0592/n)Log [(product)/(reactant)]

For the half cell reaction at the anode (silver electrode):Ag→Ag(+)+e(−). This reaction is written as a reduction reaction below:Ag(+)+e(−)→Ag Eo=0.800 volt  eq. (1)

[Ag+]=1 mg/liter*(gr/1000 mg)*(1 mol/108 (Mw of Ag))=10^(−5) Ag+mole/liter; E=0.800−(0.0592/1)log [1/(10^(−5)]. Based on this, theresulting E=8.00−(0.0592*5)=0.504 volt.

For the cathode, the reactions are:O₂+2H₂O+4c(−)→4OH(−) Eo=0.401 volt  eq. (2)O₂+4H(+)+4e(−)→2H₂O Eo=1.229 volt  eq. (3)

In dilute aqueous solutions these two reactions are equivalent. Atequilibrium the potential for the two half-cell potentials must beequal:E=0.401−(0.0592/4)log {[OH(−)]^4/[O2]}E(silver)=0.504=0.401−(0.0592/4)log {[10^−7]^4/[O2]}

Solving for [O₂], the result is: [O₂]=10^(−21) atm. The result of thisanalysis is that, thermodynamically speaking, as long as theconcentration of oxygen is above 10^(−21), the concentration of thesliver ion could remain at the presumed germicidal level.

However, a parasitic reaction to creation of silver ions is theformation of AgCl due to reaction of Cl— at the silver electrode. Thehalf-cell potential for this reaction is:AgCl+e(−)→Ag+Cl(−) Eo=0.222

Solving the Nernst equation for this reaction with E=0.504, theconcentration of chloride [Cl—]=2×10^(−5). The importance of thisreaction becomes apparent in evaluating the current needed to compensatefor the losses of current due to this reaction and the increased inratio of the area of the cathode to the anode.

The current density per until area requirements of the device can beestimated by combining Fick's and Faraday equations: the silver lossesdue to diffusion of silver from the device can be calculated using theFick's equation:j=D[C(d)−C(c)]/d  Fick's equation

The current needed to create the silver ions (A/cm2): i=j*n*F, where, jis the mass flux, C(d) is the concentration of the silver at the deviceand C(c) is concentration of silver at the capillary bed (=0). D is thediffusion coefficient of silver (10^(−6)) cm2/sec, d is the averagedistance of the device from the capillary bed (assumed to be =0.5 cm inthe bone), F is Faraday's constant (96000 col./mol), and n is the chargenumber.

The combination of the two equations for silver diffusion gives:i(Ag)=D*·n·F(C(d))/dThus:i(Ag)={10^(−6)*1*(10^(−5))*(96000)*(5*10^(−3))/0.5}*(1 liter/1000cc)=2*10^(−9)Amp/cm²

The current needed to create the silver ions at the desiredconcentration is approximately 2 nanoAmp/cm². Similarly, the currentdensity (A/cm2) required to reduce the chloride ions from biologicallevel (0.1 molar) to the desired level of 2*10^(−5) molar could becalculated. For this equation the approximate values of the constantsare D=10^(−6), d=0.1 cm. The change in the Chloride concentration itassumed to be (0.1-2*10^(−5))=0.1. The current needed to feed theparasitic reaction can then be determined:i(cl)={(10^(−6)*(1)*(96000)*((0.1)/(0.1)}*(1 lit/1000 cc)=9.6*10^(−5)=96microAmp/Cm²

The total anodic current needed is: i(Ag)+i (Cl)=i(anodic)=96microAmps/cm². On the cathode, the reaction limitation is the flux ofoxygen form the source to the surface of the electrode. The maxi(cathodic) current could be approximated to:i(O2)={(0.000324)*(4)*(96000)*(5*10^(−3))/(0.5)}(1 lit/1000cc)=1.24*10^(−3) Amps/cm²

Since the total cathodic current must be equal to total Anodic current:i(cathodic)*Area of the cathode=i(anodic)*Area of Anode⇒Area of theCathode/Area of the anode=(96*10^(−6)/(1.24*10^(−3))=0.077

This suggests that the area of the cathode must be at least equal to 8%of that of anode.

In addition to the ratio of the cathode to the ratio of the anode,another factor affecting the release of silver ions that has notpreviously been accounted for in galvanic release of silver to treatinfection is the concentration of oxygen needed.

The concentration of the oxygen needed to power the galvanic system istypically higher than that of the equilibrium concentration, since thesystem must overcome the activation energy of the reactions(over-potential) and supply the additional current. In the model belowwe evaluated the concentration of the oxygen needed to overcome theactivation energy for the reactions. Using the Tafel equation:η=β log [i/io]

where i=current density, η=the over-potential, β=overpotential voltageconstant, and io=intrinsic current density. For platinum, the oxygenover-potential constants are: β=0.05 volt and io=10^(−9) A/m². Usingi=9.6*10^ (−5) Amp then:η=0.05 log [9.6*10^(−5)/(10^(−9))]η=0.25 volt

Adding the over potential to the potential at the equilibrium (0.501volts), and the total working half-potential needed at the cathodebecomes equal to (0.501+0.25)=0.751.

Using the Nernst equation to determine the concentration of oxygen atthe cathode:E=0.751=0.401−(0.0592/4)log {[OH(−)]^4/[O2]}

Thus, the concentration of oxygen at the electrode should be at least7*10^ (−5) mole.

The results of this analysis show that an implanted galvanic systemwould benefit from having an area of the cathode to the area of theanode (A_(cathode)/A_(anode)) of greater that about 8% and theconcentration of the oxygen at the site of implant to be at least7*10^(−5) moles per liter, which may avoid rate-limiting effect.

Thus, to address the problems and deficiencies in the prior artmentioned above, described herein are systems, methods and devices (andin particular coatings, methods of coatings) for substrates thatcontrollably release antimicrobial metal ions, including apparatuses(e.g., devices and/or systems) and methods for prevent infection and foreliminating existing infections. The coatings described herein may beused as part of any appropriate substrate, including medical devices(both implanted, inserted, and non-implanted/inserted medical devices),and non-medical devices including hand-held articles. In some particularexamples, described below are implants including bioabsorbablesubstrates, and methods for using them. Also described herein aresystems, methods and devices for prophylactically treating a patient toprevent an infection and options for eliminating an existing infection,including those untreatable by any existing treatments. Described beloware implants and methods for preventing and treating bone infectionsusing an implantable, controllable, and rechargeable bone screws.

SUMMARY OF THE DISCLOSURE

In general, described herein are coatings and methods of forming andusing coatings for any substrate that will come into contact with abodily fluid and/or secretion, in which the coating may galvanicallyrelease antimicrobial ions. The coatings are configured so that therelease of the antimicrobial ions (e.g., silver, zinc and/or copper) issustained over a predetermined time period of continuous or intermittentexposure to the bodily fluid, and further so that the amount and/orconcentration of the antimicrobial ions released is above apredetermined threshold for effective antimicrobial effect eitherlocally or within a region exposed to the coating.

Although particular attention and examples of types of substrates, suchas medical devices, and in particular implantable medical deviceincluding bioabsorbable substrates, it should be readily understood thatthe coatings described herein may be used on any substrate surface thatwill come into contact with bodily fluids which would benefit from anantimicrobial effect, including devices that are not inserted orimplanted into a body. Bodily fluids are generally electricallyconductive, and may include any of: blood, blood serum, amniotic fluid,aqueous humor, vitreous humor, bile, breast milk, cerebrospinal fluid,cerumen, chyle, chyme, endolymph, perilymph, exudates, feces (diarrhea),female ejaculate, gastric acid, gastric juice, lymph, mucus (includingnasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleuralfluid, pus, rheum, saliva, sebum, semen, sputum, synovial fluid, sweat,tears, urine, vaginal secretion, vomit, etc.

As used herein, a substrate may be any surface onto which the coatingmay be applied, which may be any appropriate material, including, butnot limited to metals (e.g., alloys, etc.), ceramics, stone, polymers,wood, glass, etc., including combinations of materials. In somevariations the surface of the substrate may be prepared before thecoating is applied, as described herein. The substrate may be rigid orflexible. In particular, the coatings described herein may be applied toflexible and/or fiber-like materials such as strings, sutures, wovenmaterials, thin electrical leads, and the like. As described in greaterdetail herein, the coating typically does not inhibit the flexibility,pliability, bendability, etc. of the substrate material.

The coatings described herein typically include co-depositions of ananodic metal (e.g., one or more of zinc, silver, and/or copper) and acathodic metal (e.g., one or more of: palladium, platinum, gold,molybdenum, titanium, iridium, osmium, niobium, rhodium, manganese, andrhenium). The anodic and cathodic material in the coating arenon-uniformly dispersed within the coating, so that there are veins(e.g., microdomains or microregions, such as clusters, clumps, etc.) ofanodic metal within a matrix of cathodic metal and/or veins of cathodicmetal within a matrix of anodic metal. The relative amounts of anodicmetal in the coating may be between 20% and 80% by volume, or morepreferably between 25% and 75% by volume, or more preferably still,between 30% and 70% by volume (e.g., greater than 20%, greater than 25%,greater than 30%, etc.).

The anodic metal within the coating typically forms a continuous paththrough the coating (extending from the outer surface of the coating allthe way to the base of the coating, which may be the portion against thesubstrate), so that all or most all (e.g., greater than 80%, greaterthan 85%, greater than 90%, greater than 95%, greater than 96%, greaterthan 97%, greater than 98%, greater than 99%, etc.) of the anodic metalin the coating is interconnected, preventing entrapment of a substantialportion of the anodic metal within the coating. Similarly, the cathodicmetal within the coating may be in continuous contact throughout thecoating layer (extending from the outer surface of the coating all theway to the base of the coating, which may be the portion against thesubstrate) so that all or most all (e.g., greater than 80%, greater than85%, greater than 90%, greater than 95%, greater than 96%, greater than97%, greater than 98%, greater than 99%, etc.) of the cathodic metal inthe coating is interconnected.

As mentioned, the coatings described herein may be applied to anyappropriate substrate. For example, an apparatus that galvanicallyreleases antimicrobial ions may include: a substrate; and a coating onthe substrate comprising an anodic metal (that has been co-depositedwith a cathodic metal on the substrate) to form a non-uniform mixture ofthe anodic and cathodic metals, wherein the coating comprises aplurality of microregions or microdomains of anodic metal in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal, the microregions ormicrodomains forming a continuous path of interconnected veins of anodicmetal within the matrix of cathodic metal or a continuous path ofinterconnected veins of cathodic metal within the matrix of anodicmetal, wherein the continuous path extends from an outer surface of thecoating to the substrate; further wherein the anodic metal isgalvanically released as antimicrobial ions when the apparatus isinserted into a subject's body.

The substrate may be an implant configured to be inserted into a humanbody, including a medical device. The substrate may be device configuredto be temporarily or permanently inserted into the body (e.g., surgicaltools, implants, etc.). In some variations the substrate may be a deviceconfigured to be worn on a human body (e.g., jewelry, clothing, surgicalgowns, masks, gloves, etc.). The substrate may be a structure configuredto hold, support and/or house a subject (e.g., gurney, chair, bed,etc.). The coating may be applied to all or a portion of the substrate,particularly those surfaces of the substrate that may be placed incontact with a bodily fluid (e.g., a handle, supporting surface, etc.).The substrate may be a household item, such as a cutlery (e.g., spoons,baby spoons, forks, etc.), food handling items (e.g., platters, plates,straws, cups, etc.), handles (e.g., doorknobs, pushes, etc.), faucets,drains, tubs, toilets, toilet knobs, light switches, etc.

The anodic metal may be any combination of the anodic metals describedherein (e.g., zinc, silver, copper, both zinc and silver, etc.). Theanodic metal may be least about 30 percent by volume (or in somevariations, by weight, e.g., when the densities of anodic and cathodicmaterials are similar) of the coating.

The cathodic metal may generally have a higher galvanic potential thanthe anodic metal. This may drive the galvanic (e.g., “corrosion”) of theanodic metal when the coating is exposed to a bodily fluid. For example,the cathodic metal may comprise one or more of: palladium, platinum,gold, molybdenum, titanium, iridium, osmium, niobium, rhodium,manganese, and rhenium.

The coating may be formed by vapor deposition. For example, the anodicmetal and the cathodic metal may have been vapor-deposited onto thesubstrate so that the anodic metal is not encapsulated by the cathodicmetal, e.g., so that the anodic metal (and/or in some variations thecathodic metal) include veins that extend continuously through thecoating from the outer surface to the base (e.g., the “bottom” of thecoating adjacent to the substrate) of the coating. Thus, the continuouspath of interconnected veins may be interconnected so that less than 15%of the anodic metal is completely encapsulated within the matrix ofcathodic metal, or less than 15% of the cathodic metal is completelyencapsulated within the matrix of anodic metal. The continuous path ofinterconnected veins may be interconnected so that less than 10% of theanodic metal is completely encapsulated within the matrix of cathodicmetal, or less than 10% of the cathodic metal is completely encapsulatedwithin the matrix of anodic metal.

An apparatus that galvanically releases antimicrobial ions may include:a substrate; and a coating on the substrate comprising zinc and silverand a cathodic metal that are all co-deposited onto the substrate,wherein the zinc and silver are at least about 25 percent by volume (orin some variations by weight) of the coating and form a non-uniformmixture of the zinc and the cathodic metal and a non-uniform mixture ofthe silver and the cathodic metal, wherein the coating comprises aplurality of microregions or microdomains of zinc and silver in a matrixof cathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of zinc and a matrix of silver, themicroregions or microdomains forming a continuous path of interconnectedveins of zinc and silver within the matrix of cathodic metal or acontinuous path of interconnected veins of cathodic metal within thematrix of zinc and the matrix of silver, wherein the continuous pathsextend from an outer surface of the substrate; further wherein the zincand silver are galvanically released as antimicrobial ions when theapparatus is inserted into a subject's body.

In some variations, the substrate may be bio-absorbable. For example, insome variations, the substrate is configured to degrade within the bodyto form a degradation product including an anion that complexes withions of the anodic metal and diffuses into the subject's body to form anantimicrobial zone. For example, a bioabsorbable apparatus thatgalvanically releases antimicrobial ions may include: an implant havingan outer surface comprising a substrate; and a coating on the substratecomprising an anodic metal that is co-deposited with a cathodic metal onthe substrate to form a non-uniform mixture of the anodic and cathodicmetals, wherein the coating comprises a plurality of microregions ormicrodomains of anodic metal in a matrix of cathodic metal or aplurality of microregions or microdomains of cathodic metal in a matrixof anodic metal, the microregions or microdomains forming continuouspaths of interconnected veins of anodic metal within the matrix ofcathodic metal or continuous paths of interconnected veins of cathodicmetal within the matrix of anodic metal, wherein the continuous pathsextend from an outer surface of the coating to the substrate; furtherwherein the anodic metal is galvanically released as antimicrobial ionswhen the apparatus is inserted into a subject's body.

Thus, also described herein are bioabsorbable substrates, andparticularly bioabsorbable filaments, that galvanically releaseantimicrobial ions. The bioabsorbable filament is coated with an anodicmetal (such as silver, copper and/or zinc) that has been co-depositedwith a cathodic metal (such as platinum, gold, palladium) along at leasta portion of the length of the filament. The filament retains itsflexibility. After insertion into the body, the anodic metal corrodes asthe filament is bioabsorbed. The degradation of the filament may createa local pH that enhances the release of the silver and/or copper and/orzinc ions.

In general, the coated filaments may be arranged into structures (e.g.,sutures, mesh, slings, yarns, etc.) that can be implanted into the body.

As mentioned, the anodic and cathodic metals forming the coatingsdescribed herein are typically co-deposited together, and not coated inlayers (e.g., atop each other). For example, the metals may be jointlyvapor deposited. Examples of jointly deposited anodic and cathodicmaterials include silver-platinum, copper-platinum, zinc-platinum,silver-gold, copper-gold, zinc-gold, etc. Different types of jointlydeposited anodic and cathodic metals may be arranged on the bioabsorblesubstrate. For example, silver-platinum may be coated near (either nottouching or touching) a region of zinc-platinum; different co-depositedanodic/cathodic metals may be a spacer region on the substrate.

In some variations, described herein are devices and methods forpreventing an infection in an implantable device such as a pacemaker ora defibrillator when inserting it into a body by incorporatingbioabsorbable materials that galvanically releaseantimicrobial/antibacterial metals such as silver and/or zinc and/orcopper. For example, an implant may be inserted into a woven mesh madeof a bioabsorbable material that is coated (or impregnated) with ananti-microbial anodic metal ions such as silver or zinc co-depositedwith a catalytic cathodic metal such as platinum, gold, or palladium.

In general, as mentioned above, the anodic metal may be silver, zinc, orany other metal with germicidal activity, and the cathode metal may beplatinum, gold, palladium, or any other metal with catalytic action,including molybdenum, titanium, iridium, osmium, rhodium, manganese,niobium and rhenium. The biodegradable substrate may be a biodegradablefilament, such as polylactic acid (PLA), poly(lactic-co-glycolic acid)(PLGA), polyglycolide (PGA), polyglycoside-co-trimethylene carbonate(PGTMC), poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL). As used herein the terms biodegradable andbioabsorbable may be used interchangeably.

For example, described herein are biodegradable filaments that may beformed into an envelope, pouch, pocket, etc. (generically, aco-implantable structure) made of a biodegradable polymer (such as PLGA,PGA, PLA, polycaprolactone, etc.). The implant may be co-implanted withthe co-implantable structure, for example, by placing the mesh onto theimplant before, during or after insertion into the body. Theco-deposited metal coating of the co-implantable structure creates agalvanic system resulting in release of germicidal ions protecting thedevice from getting infected in the body once the device is implantedwith the structure into a body. In the semi-aqueous environment of thebody, the metal will corrode over time by releasing the ions (e.g.,silver ions, copper ions, zinc ions, etc.). A coated bioabsorbablepolymer could also or alternatively be used as an insert inside thelumen of the device such as a cannula, cannulated screw, or as a coatingon a device. In another configuration the metal ions could be coupledwith a poly-anionic (negatively charged) polymer and mixed with thepolymer.

For example, described herein are bioabsorbable apparatuses thatgalvanically release antimicrobial ions. The apparatus may comprise: aflexible length of bioabsorbable filament; and a coating on the lengthof filament comprising an anodic metal that is co-deposited with acathodic metal on the length of filament; wherein the coated filament isflexible; further wherein the anodic metal is galvanically released asantimicrobial ions when the apparatus is inserted into a subject's body.

In general, in apparatuses (systems and devices) in which the anodicmetal and the cathodic metal are co-deposited (e.g., by vapordeposition) the anodic metal may be at least about 25 percent (e.g., atleast about 30 percent, at least about 35 percent, etc.) by volume ofthe coating. This may prevent complete encapsulation of the anodicmaterial (e.g., zinc, silver, etc.) by the cathodic material (e.g.,palladium, platinum, gold, molybdenum, titanium, iridium, osmium,niobium, rhodium, manganese, and rhenium). As described in greaterdetail below, the coatings applied may be configured to result inmicroregions or microdomains of anodic material in a matrix of cathodicmaterial. The microdomains may be interconnected or networked, or theymay be isolated from each other. In general, however, the concentrationsof anodic material and cathodic material may be chosen (e.g., greaterthan 25% by volume of the anodic material, between about 20% and about80%, between about 25% and about 75%, between about 30% and about 70%,etc.) so that the majority of the anodic material in the coatingthickness is connected to an outer surface of the coating, allowingeventual corrosion of most, if not all of the anodic metal asanti-bacterial metal ions, while providing sufficient cathodic materialto provide adequate driving force for the corrosion of the anodicmaterial. Thus, the coating may comprise the anodic metal and thecathodic metal that have been vapor-deposited onto the length offilament so that the anodic metal is not encapsulated by the cathodicmetal.

As mentioned, the anodic metal may comprise zinc, copper or silver, orin some variations both zinc and silver. In general, the cathodic metalhas a higher galvanic potential than the anode. For example, thecathodic metal may be one or more of: palladium, platinum, gold,molybdenum, titanium, iridium, osmium, rhodium, manganese, niobium andrhenium.

As mentioned, in general the bioabsorbable substrate (e.g., filament)may comprise one or more of: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL).

In general, the bioabsorbable substrate (including a length ofbioabsorbable filament) is configured to degrade within the body to forma degradation product, including an anion that complexes with ions ofthe anodic metal and diffuses into the subject's body to form anantimicrobial zone.

The bioabsorbable substrate (e.g., bioabsorbable filament) may beconfigured as a mesh, bag, envelope, pouch, net, or the like, that maybe configured to hold an implant. For example, the flexible structuremay be configured to at least partially house a pacemaker,defibrillator, neurostimulator, or ophthalmic implant.

Also described herein are bioabsorbable apparatuses that galvanicallyrelease antimicrobial ions and comprise: a plurality of lengths ofbioabsorbable filament arranged in a woven structure; and a coating onthe lengths of filament comprising zinc and silver and a cathodic metalthat are all co-deposited onto the lengths of filament, wherein the zincand silver are at least about 25 percent by volume of the coating;further wherein the zinc and silver are galvanically released asantimicrobial ions when the apparatus is inserted into a subject's body.As mentioned, the woven structure may form a mesh, bag, envelope, pouch,net, or other structure that is configured to at least partially enclosean implant within the subject's body.

Also described herein are bioabsorbable apparatuses that galvanicallyreleases antimicrobial ions and include: a plurality of lengths ofbioabsorbable filament; and a coating on the lengths of filamentcomprising an anodic metal that is co-deposited with a cathodic metal onthe lengths of filament; wherein the lengths of filament are arrangedinto a flexible structure; further wherein the anodic metal isgalvanically released as antimicrobial ions when the apparatus isinserted into a subject's body.

Methods of forming any of these apparatuses are also described,including methods of forming a coated bioabsorbable substrate, forexample, by co-depositing (vapor depositing) an anodic material and acathodic material onto the substrate. The substrate may be a fiber orthe structure formed of the fiber. In some variations the method mayalso include forming different regions of co-deposited anodic andcathodic materials, wherein the different regions include differentcombinations of anodic and cathodic materials. The different regions maybe non-contacting. In general, co-deposing anodic and cathodic materialsare typically performed so that the anodic material forms greater than25% by volume of the coating, preventing encapsulation of the anodicmaterial by cathodic material within the coating.

Also described are methods of treating a subject using the bioabsorbablematerials that are co-deposited with one or more coating of anodic andcathodic metals (e.g., materials). For example, described herein aremethods of galvanically releasing antimicrobial ions to form anantimicrobial zone around an implant that is inserted into a subject'stissue. The method may include step of: inserting into the subject'stissue an apparatus comprising a plurality of lengths of bioabsorbablefilament having a coating comprising an anodic metal and a cathodicmetal that are co-deposited onto the lengths of filament, wherein theimplant is at least partially housed within the apparatus; galvanicallyreleasing antimicrobial ions from the coating (e.g., galvanicallyreleasing ions of silver and zinc); allowing the lengths of filament todegrade into a degradation product including anions, wherein the anionscomplex with antimicrobial ions of the anodic metal and diffuse into thetissue to form an antimicrobial zone around the implant. The method mayalso include inserting an implant into the apparatus before theapparatus is inserted into the subject's body. For example, insertingthe apparatus into the body may comprise inserting a flexible apparatuscomprising the plurality of length of bioabsorbable filaments forming abag, envelope, pouch, net or other structure (woven or otherwise) formedto hold the implant. For example, the method may also include insertinga pacemaker, a defibrillator or a neurostimulator into the apparatus.

Inserting the apparatus may comprise inserting the apparatus having aplurality of lengths of bioabsorbable filaments coated with the anodicmetal that comprises silver and zinc that are co-deposited onto thelengths of filament with the cathodic metal.

Allowing the lengths of filament to degrade may comprise degrading thelengths of filament into anions that bind to silver ions from thecoating. For example, inserting the apparatus comprises inserting theapparatus having a plurality of lengths of bioabsorbable filamentscoated with the anodic metal that is co-deposited onto the lengths offilament with the cathodic metal, wherein the anodic metal is at leastabout 25 percent by volume of the coating (e.g., at least about 30%, atleast about 35%, etc.).

Inserting the apparatus comprising the plurality of lengths ofbioabsorbable filament may comprise inserting the apparatus having aplurality of lengths of one or more of: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), and polyglycolide (PGA).

In general, the antimicrobial zone around the implant may be sustainedfor at least seven days.

Also described herein are apparatuses that galvanically releasesantimicrobial ions and include: a substrate; and a coating on thesubstrate, the coating comprising a mixture of between about 25% and 75%by volume of an anodic metal and between about 25% to 75% by volume of acathodic metal co-deposited on the substrate, wherein the coatingcomprises a plurality of microregions or microdomains of anodic metal ina matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming interconnected veins of anodicmetal through the coating thickness, or an interconnected veins ofcathodic metal through the coating thickness, wherein the paths extendfrom an outer surface of the coating through the coating to an oppositeside of the coating; wherein the anodic metal is galvanically releasedas antimicrobial ions when the apparatus is exposed to a bodily fluid.

In general, these coatings may be formed in a pattern on the substrate.For example, the coating may form one or more of: a sinusoidal pattern,cross-hatched pattern, a mesh pattern, a web pattern, or a zig-zagpattern.

As discussed above, any appropriate substrate may be used, including oneor more of: a cloth, a surgical drape, a catheter, an outer housing of asurgical implant, a pacemaker, defibrillator, neurostimulator, orophthalmic implant. The substrate may comprise a surface of one of: animplantable shunt, an artificial joint, a hip implant, a knee implant, astent, an implantable coil, a pump, an intrauterine device (IUD), aheart valve, a surgical fastener, a surgical staple, a surgical pin, asurgical screw, an implantable electrical lead, or an implantable plate.

For example, described herein are apparatuses that galvanically releasesantimicrobial ions, the apparatus comprising: a substrate; and apatterned coating on the substrate, the patterned coating comprising amixture of between about 25% and 75% by volume of an anodic metal andbetween about 25% to 75% by volume of a cathodic metal co-deposited onthe substrate, wherein the coating comprises a plurality of microregionsor microdomains of anodic metal in a matrix of cathodic metal or aplurality of microregions or microdomains of cathodic metal in a matrixof anodic metal, the microregions or microdomains forming interconnectedveins of anodic metal through the coating thickness, or aninterconnected veins of cathodic metal through the coating thickness,wherein the paths extend from an outer surface of the coating throughthe coating to an opposite side of the coating, wherein the patternedcoating includes one or more of: a sinusoidal pattern, cross-hatchedpattern, a mesh pattern, a web pattern, or a zig-zag pattern, furtherwherein the anodic metal is galvanically released as antimicrobial ionswhen the apparatus is exposed to a bodily fluid.

Also described herein are methods of galvanically releasingantimicrobial ions from a coated surface, comprising: contacting thecoated surface with a bodily fluid, wherein the coated surface comprisesa coating having a mixture of between about 25% and 75% by volume of ananodic metal and between about 25% to 75% by volume of a cathodic metalco-deposited on the surface, further wherein the coating comprises aplurality of microregions or microdomains of anodic metal in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal, the microregions ormicrodomains forming a path of interconnected veins of anodic metalthrough the coating thickness, or a path of interconnected veins ofcathodic metal through the coating thickness, wherein the path extendsfrom an outer surface of the coating through the coating to an oppositeside of the coating; and galvanically releasing antimicrobial ions ofthe anodic metal from the coating.

Contacting the coated surface may include contacting a surface having apattern of coating, wherein the pattern is one or more of a sinusoidalpattern, cross-hatched pattern, a mesh pattern, a web pattern, or azig-zag pattern. In this way, the entire surface does not need to becoated, though the antimicrobial ions may be release in a larger regionto a larger field of antimicrobial protection, particularly whenapparatuses including the coatings are inserted or implanted into abody.

For example contacting the coated surface may include contacting asurface of a one or more of: a cloth, a surgical drape, as surgicalinstrument cover, a surgical instrument, a catheter, an outer housing ofa surgical implant, a pacemaker, defibrillator, neurostimulator, orophthalmic implant, an implantable shunt, an artificial joint, a hipimplant, a knee implant, a stent, an implantable coil, a pump, anintrauterine device (IUD), a heart valve, a surgical fastener, asurgical staple, a surgical pin, a surgical screw, an implantableelectrical lead, an implantable plate, a handle, a cage, or an item ofcutlery.

Contacting the coated surface with the bodily fluid may includeimplanting an apparatus including the coated surface into a patient'sbody. In some variations, contacting the coated surface with the bodilyfluid comprises touching the coated surface with a bare skin surface.

In addition to the cathode metals for any of the apparatuses (devices,systems, etc.) described herein my include manganese as the cathodemetal or as one of the cathode metals. In particular, any of the cathodemetals (e.g., for the coatings) may include a combination of platinumand manganese, or palladium and manganese, or a combination of allthree. For example, the coating may be applied by sputter platinum,palladium and manganese, and these metals could be co-sputtered at thesame time with the anode metal (e.g., Ag).

Also described herein are systems, devices and methods that maygenerally be used to treat or prevent infection, including boneinfections such as osteomyelitis by the controlled release of silver,zinc, or silver and zinc ions. In particular, the systems, methods anddevices described herein may be configured to allow controllablegalvanic release of ions (e.g., silver, zinc or silver and zinc ions) totreat or prevent infection. Many of the variations described herein maybe used in conjunction with one or more implants that also structurallyor therapeutically support the patient, including particularly thepatient's bones.

In general, any of the implants described herein may be used to treatbone and/or soft tissue. In some variations the implants are boneimplants specifically, and may be configured to support as well as treatthe bone. For example, the implant may be used to secure (as a screw,nail, bolt, clamp, etc.) another member such as a plate, rod, or thelike, or the implant may itself include a support member such as a rod,plate, etc. In some variations, the implant is a soft tissue implantthat is configured to be secured within non-bone body structures.

Although many of the examples described herein are illustrateddescribing the release of silver ions, any of the devices, methods andsystems described may be configured for the release of zinc ions insteadof, or in addition to, silver ions. It may be beneficial to release bothzinc and silver ions. In some situations it may be beneficial to releasezinc rather than silver, or vice versa. For example, variations of thedevices releasing zinc may be used preferentially when the infectiontargeted is resistant to silver. Zinc may also “corrode” faster, e.g.,releasing ions more quickly and/or at a higher concentration thansilver, which may be avoided or exploited depending upon the context.

Described herein are systems, devices and methods for the controlledrelease of silver, zinc, or silver and zinc ions to treat or preventinfection that may address many of the problems identified above. Forexample, described herein are devices configured for the galvanicrelease of ions that may be controlled with an on/off switch mechanism.For example, in some variations the galvanic relationship can beregulated remotely (before or after the silver and/or zinc releasingimplant has been inserted into the body). In some variations the systemsand device may be configured so that the implant includes a separable orseparate cathode and/or anode. The anode region (e.g., silver, zinc, orsilver and zinc anode) may be placed central to the treatment regionwhile the cathode could be positioned in an oxygen-rich region that maybe separate from the treatment region (e.g., oxygenated blood). This mayallow effective treatment of even relatively anoxic regions, includingbone.

The devices and systems described herein may also be configured toregulate the effective cathode active surface area and anode activesurface area (e.g., making the cathode surface area much larger than theeffective anode surface area). For example, the cathode active surfacearea may be 5% greater (e.g., Au/Palladium), 8% (e.g., Au/Pt), 10%(e.g., Au/Ag), etc. than the anode surface area.

For example described herein are implants, including bone implants, forproviding antimicrobial treatment to a region of a bone (and/orsurrounding tissues) In some variations the implant includes: anelongate cannulated body having a threaded outer region; at least oneexit channel extending from the cannulated body and out through thethreaded outer region; and one or more silver, zinc, or silver and zincrelease members configured to extend from the cannulated body and out ofthe exit channel.

The ion release members may be configured as part of a removabletreatment cartridge that is configured to fit within the cannulated bodyof the implant so that the one or more ion release members extend fromthe cannulated body. Note, as used herein the phrase “treat” and“treatment” may include acute and prophylactic treatments.

In the simplest variation, the implant is configured as a bone screwthat is hollow or contains a hollow inner body region into which areplaceable/rechargeable treatment cartridge may be inserted and/orremoved. The cartridge may be itself screwed into the body, or it may beotherwise secured within the body. The cartridge may include one or more(e.g., a plurality) of ion release members extending or extendable fromthe cartridge and therefore the implant. An ion release member may beconfigured to release silver, zinc or silver and zinc. In general an ionrelease member may be configured as an elongate member such as an arm,wire, branch, or the like. The ion release member may be a wire (e.g.,silver wire), or it may be a coated member such as a Nitinol or othershape-memory member, including a silver and/or zinc coating. Asmentioned, the implant (or the treatment cartridge portion) may includea plurality of ion release members.

An implant may have one or more exit channels. In general the exitchannels may be openings from the inner hollow region (e.g. cannulatedbody) of the implant through a side wall of the implant and out,possibly in the threaded region. Thus, in some variations the exitchannel is configured to deflect the one or more ion release membersaway from a long axis of the implant. For example, the exit channel maybe configured to deflect the one or more ion release members against athread of the outer threaded region so that it deflects away from theimplant. In some variations a plurality of exit channels extendingthrough the cannulated body.

An implant may also include a guide (or guide element, including a rail,keying, etc.) within the channel configured to guide or direct the oneor more ion release member out of the cannulated body from the at leastone exit channel. The exit channels may be configured to allow tissue(e.g., bone) ingrowth, which may help with stability of the device onceimplanted. For example, the exit channels may be slightly oversizedcompared to the ion release members, permitting or encouragingin-growth. In some variations the exit channels may be doped orotherwise include a tissue-growth enhancing or encouraging factor (suchas a growth factor), or may be otherwise modified to encourage tissuegrowth.

In some variations the treatment cartridge may include a silver, zinc orsilver and zinc anode and the elongate body includes a cathode, whereinthe cathode has a higher redox potential than the anode. The cathode mayhave an irregular surface, or a high-surface area (e.g., per unitvolume); for example, the cathode may be formed of a foamed metal. Ingeneral the surface area of the cathode may be substantially greaterthan the surface are of the anode.

The treatment cartridge may be replaceable. For example, a treatmentcartridge may be configured to be removable from the cannulated body ofthe implant in situ, without removing the body of the implant from thedevice. Thus, the body of the implant may be structurally supportive(e.g., supporting the bone) while the silver-releasing portion may bere-charged by inserting another (replacement) cartridge after theprevious cartridge has corroded. For example, an elongate cannulatedbody may be configured as bone screw (e.g., an intramedullary bonescrew).

In some variations, an implant for providing antimicrobial treatment toa tissue includes: an elongate body having a threaded outer screwregion; an inner channel within the elongate body; a plurality of exitchannels extending from the inner channel and out through the threadedouter screw region; and a treatment cartridge configured to fit withinthe inner channel, the cartridge comprising a plurality of ion releasemembers configured to extend out of the exit channels.

As mentioned, the inner channel may include a guide element configuredto direct the release members out of the exit channels. The guideelement may be a shaped channel region (e.g., keying) or the like,configured to regulate the interaction between the implant body and thecartridge.

Any of the variations described herein may also include a tissuesampling feature. For example, the treatment cartridge may comprise asampler element configured to obtain a sample from a patient in whom abone implant has been implanted. A sampler element may be a regionconfigured to scrape, cut or otherwise remove a sample of tissue,particularly as the cartridge is removed from the implant. The sampledtissue may be examined for infection or the like.

Also described herein are systems for the controllable galvanic releaseof silver, zinc or silver and zinc ions from an implant to prevent ortreat infection. For example, a system may include: a threaded implantconfigured to be inserted into a bone and to hold an ion releasingtreatment cartridge; a cathode on the implant, the cathode comprising amaterial having a higher redox potential than the material of the anode(e.g., silver, zinc or silver and zinc); a treatment cartridgecomprising a silver, zinc or silver and zinc anode, wherein, when thetreatment cartridge is held by the implant, the cathode is in electricalcontact with the anode, driving the galvanic release of ions from therelease cartridge; and a switchable control configured to regulateelectrical contact between the anode and cathode.

In any of the variations described herein, the cathode may comprise amaterial selected from the group consisting of: palladium, platinum, andgold. The cathode and anode may be configured to generate a galvaniccurrent greater than about 0.2 μamps. The treatment cartridge mayinclude a plurality of ion release members configured to extend from theimplant when the cartridge is engaged therewith.

As mentioned above, any of the variations described herein may include aswitchable control configured to turn on and/or off the galvanicactivity between the anode and cathode. In some variations the switchmay be configured to electrically separate the anode and cathodepreventing or limiting the galvanic reaction. In some variations, theswitchable control may be configured for remote activation. For example,a switchable control may include a magnet.

Also described herein are methods of controllably delivering silver ionsfrom an implant to prevent or treat infection. Such a method may includethe steps of: engaging an implant with a removable ion-releasingtreatment cartridge, wherein the treatment cartridge comprises an anode(silver, zinc or silver and zinc), and wherein the implant includes acathode comprising a material having a higher galvanic potential thanthe anode, further wherein the cathode has a greater active surface areathan the active surface area of the anode; and activating a switchablecontrol to initiate the galvanic release of ions from the treatmentcartridge by placing the cathode in electrical contact with the anode.

The step of engaging the implant with the removably treatment cartridgemay include coupling the treatment cartridge with an implant alreadyinserted into a patient. The method may also include the step of placingat least a portion of the cathode in communication with a source ofoxygen at a concentration of greater than 7×10−5 mol/L. In somevariations, the implant may be implanted into a bone.

Also described are systems for the release of ions from an implant toprevent or treat infection, the system including: an implant configuredto hold a silver, zinc or silver and zinc release treatment cartridge; aremovable treatment cartridge comprising a silver, zinc or silver andzinc anode; and a cathode comprising a material having a higher redoxpotential than the anode, wherein the cathode is configured to bepositioned separately from the anode and in contact with an oxygen-richenvironment when the implant is implanted; wherein, when the treatmentcartridge is held by the implant, the cathode is in electrical contactwith the anode, driving the galvanic release of ions from the treatmentcartridge.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIGS. 1A-1F illustrate the general concept of galvanic release of silverions.

FIG. 2A shows a cross-sectional view through one example of a substratehaving a combined coating, comprising an anodic metal that isco-deposited with a cathodic metal.

FIG. 2B is a schematic representation of an enlarged view of a portionof the coated substrate of FIG. 2A, schematically illustratingmicro-domains or veins of anodic metal (not to scale) within a cathodicmatrix.

FIG. 2C is another schematic representation of an enlarged view of aportion of the coated substrate of FIG. 2A.

FIG. 2D is an example of the galvanic release (and corrosion) of acoating on a substrate such as the one shown in FIG. 2A.

FIGS. 3A-3C illustrate top views of alternative variations of coatingpatterns for different combined coatings, such as silver/platinum andzinc/platinum.

FIG. 4 is an example of a bioabsorbable pouch woven from one or morestrands, wherein the strands of the pouch are coated with the combinedcoatings described herein for release of antimicrobial ions.

FIG. 5A illustrates a fiber or filament (e.g., suture fiber) coated witha striped pattern of a combined coating for galvanic release of metalions.

FIG. 5B illustrates a portion of a barbed suture fiber coated asdescribed herein.

FIG. 5C is a portion of a suture fiber that is coated as describedherein.

FIG. 5D is an example of a needle and suture (shown as a combined needlepreloaded with suture) in which both needle and suture are coated asdescribed herein.

FIG. 6 is an example of a length of suture formed from a bioabsorbablesubstrate onto which a combined coating has been regionally applied(e.g., near the distal end).

FIG. 7 illustrates one example of a medical device configured as atransvaginal mesh having a combined coating for release of metal ionsafter insertion into the body.

FIG. 8A is a side perspective view of one example of a plug or patchthat may be used, e.g., to repair a hernia. The device is coated withmultiple types of combined coatings for galvanic release of metal ions.

FIG. 8B shows an enlarged view of one region of the plug.

FIG. 9 is a perspective view of one variation of a bandage or patchincluding a combined coating, shown on a patient's knee.

FIG. 10 illustrates one variation of an artificial dura (mesh) includinga combined coating for galvanic release of metal ions.

FIG. 11 shows an example of a material that may be used as within awound or surgical site to prevent or treat infection. The material maybe a porous and/or bioabsorbable mesh that is configured to galvanicallyrelease metal ions.

FIGS. 12A and 12B show side perspective and end views, respectively ofone variation of a cannula including a pattern of a combined coating forthe release of antimicrobial metal ions.

FIGS. 13A and 13B illustrate one example of a medical device (animplantable pacemaker) that may be used with the co-deposited galvaniccoatings described herein.

FIG. 13C is a schematic depiction of a conventional cardiac stimulationand defibrillation arrangement.

FIGS. 14A and 14B illustrate another example of a medical device (avenous catheter) that may be coated with the co-deposited galvaniccoatings described herein.

FIGS. 15A and 15B show an example of a catheter (including a cuff) thatmay include a galvanically released antimicrobial coating that isco-deposited as described herein.

FIG. 15A is an example of a triple lumen device and FIG. 15B is anexample of a dual lumen device.

FIG. 16 shows one example of a catheter that has been coated byco-deposition of the galvanic coating described herein.

FIG. 17A shows a cannulated bone screw that may be used with a coatedinsert as shown in FIG. 17B. The coated insert may be a bioabsorbablemesh, coated as described herein.

FIG. 17C shows the bone screw of FIG. 17A with the mesh of FIG. 17Binserted.

FIG. 18A shows a bone screw coated as described herein.

FIG. 18B shows a bone screw similar to that shown in FIG. 18A, but whichhas been coated in a striped pattern (e.g., having regions that areeither uncoated, or coated with different anionic materials/combinationsof materials, as described in FIGS. 3A-3C, above.

FIG. 19A is another example of bone screw implant having openings orchannels from which members (shown extending in FIG. 19B) may extend.Either or both the bone screw and the extending members may be coated asdescribed herein.

FIG. 20 shows an example of an animal cage coated as described herein.

FIG. 21 shows an example of a doorknob coated as described herein.

FIG. 22A shows an example of cutlery (a fork and spoon) coated asdescribed herein.

FIG. 22B shows another example of spoon coated as described herein.

FIG. 23A show a cross-sectional view through an example of a substratesurface having a coating comprising an anodic metal co-deposited with acathodic metal, in which the coating has been cracked, enhancingavailable surface area, as described herein.

FIG. 23B is a schematic representation of an enlarged view of a portionof the coated substrate of FIG. 23A, schematically showing (not toscale) micro-domains or veins of anodic metal within a cathodic matrix,showing cracks in the coating.

FIGS. 24A-24C illustrate exemplary patterns of coatings that may bemade. FIG. 24A shows an example of a cross-hatched pattern that may beformed on a substrate, including a tube or catheter, by masking. FIG.24B illustrates an example of a diagonal hatched pattern of coating asdescribed herein that may be coated on a substrate, including a catheteror tubing. FIG. 24C illustrates another example of a sinusoidal patternof coating.

FIGS. 25A and 25B illustrate an example of a surgical drape including anantimicrobial coating as described herein, configured as a drape for asurgical instrument. In FIG. 25A the draping shown may be coated withthe antimicrobial coating described herein, and the draping applied overan endoscope. FIG. 25B shows another endoscope, attached to a monitor,including a surgical drape.

FIG. 26 shows an example of a drape for use in a sterile medical fieldthat has been coated with the antimicrobial coating as described herein;in this example the drape covers a robotic medical device.

FIG. 27 shows a medical microscope covered with a drape or cover coatingas described herein.

FIG. 28 is an example of a cover/handle for a surgical light that hasbeen coated as described herein.

FIG. 29 illustrates an example of a surgical instrument cover includinga coating as described herein.

FIGS. 30A and 30B show examples of surgical instrument covers (shown assurgical drills in this example) that may be coated with any of theantimicrobial coatings described herein.

FIG. 31 is an example of a cover for an ultrasound probe that has beencoated as described herein.

FIGS. 32A and 32B illustrate one variation of an implant as describedherein.

FIG. 33 shows another variation of an implant as described herein.

FIG. 34 shows the implant of FIG. 33 in a deployed configuration.

FIG. 35 is another variation of an implant.

FIG. 36 is another variation of an implant.

FIGS. 37A-37C illustrate deployment of a silver eluting bone implant asdescribed herein.

FIGS. 38A and 38B illustrate deployment of another silver eluting boneimplant.

FIGS. 39A and 39B show a top view of an implant in a deployed anun-deployed configuration.

FIGS. 40A-40D illustrate variations of silver eluting bone implants asdescribed herein.

FIGS. 41A-41C illustrate another variation of an implant.

FIG. 42A shows another variation of a silver-eluting implant in adeployed and activated configuration (e.g., with silver release membersextended into the tissue) and FIG. 42B shows the same implant in ade-activated configuration, in which the silver release members havebeen withdrawn into the lumen/channel of the implant.

FIGS. 43A and 43B illustrate two variations of silver eluting boneimplants as described.

FIG. 44 illustrates another variation of an implant configured for useas a dental device. Similarly, FIGS. 45 and 46 illustrate variations ofsilver eluting bone implants configured to treat other bone regions,including the jaw and skull (face), respectively.

DETAILED DESCRIPTION

In general, described herein are apparatuses (e.g., systems and devices)that include a coating or layer that galvanically releases antimicrobialions over an extended period of time. The coating may be applied to asubstrate, e.g., a bioabsorbable and/or biodegradable substrate that maydegrade during the same period that the antimicrobial ions are beingreleased, e.g., days, months, years. In some variations the substratemay be coated with an adhesion layer on the substrate. The substrate maybe pre-treated (e.g., to remove oxides, such as the titanium oxide layeron a nickel titanium substrate). In general, the coating may include acombination of anodic metal, such as silver and/or zinc and/or copper,and a cathodic metal, such as palladium, platinum, gold, molybdenum,titanium, iridium, osmium, niobium, rhodium, manganese and rhenium,where the anodic metal and cathodic metals are co-deposited (e.g., byvapor deposition) so that the anodic metal is exposed to an outersurface of the coating and not fully encapsulated in the cathodic metal,and there is sufficient cathodic metal to drive the galvanic release ofanodic ions when exposed to bodily fluids such as blood, lymph, etc.(e.g., when implanted into the body).

For example, described herein are apparatuses including substrates ontowhich anodic metal and cathodic metals are co-deposited to form acoating, allowing the anodic metal to be galvanically released as ions(e.g., antimicrobial silver, copper and/or zinc ions) when the apparatusis exposed to a conductive fluid (e.g., a bodily fluid). The substratemay include an adhesive coating (such as a tantalum or titanium layerthat is applied before the galvanic coating of co-deposited antic andcathodic metal).

Galvanically Releasable Coating

In general, the antimicrobial metal ion coatings described herein aregalvanically releasable within a tissue, and include one or more anodicmetal (typically silver and/or zinc and/or copper) that is co-depositedwith a cathodic metal (typically platinum and/or palladium). The anodicmetal and the cathodic metal are co-deposited, e.g., by sputtering orother appropriate methods described herein, so that the resultingcoating is non-homogenous, with a percentage of anodic metal (e.g.,silver) that is greater than about 30% co-distributed (typically inclusters, veins or clumps as illustrated and described below) with thecathodic metal (e.g., platinum), where the cathodic metal is greaterthan about 30% (e.g. % w/w) of the coating. The antimicrobial metal ioncoatings described herein may be generally referred to as non-homogenousmixtures where the anode is distributed in connected clusters (veins)within the cathodic metal (or vice-versa). Generally, both the anodicmetal and the cathodic metal are exposed in microdomains across theouter surface of the coatings, allowing galvanic release; as the anodicmetal is released, it may form channels (e.g., tunnels, mines, etc.)through the coating, e.g., within the cathodic material. In somevariations the cathodic material remains behind. In some variations someof the cathodic material may also be released.

Thus, in any of these variations, the coating may comprise a non-uniformmixture of the anodic and cathodic metals, with a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal, and/or a plurality of microregions or microdomains of cathodicmetal in a matrix of anodic metal. These microregions or microdomainsmay be formed by co-deposition as described herein.

Any of the coatings described herein may include co-deposited multipleanodic and/or multiple cathodic metals forming the coating. In somevariations, it may be preferable to separate regions having a firstanodic metal (e.g., silver) from regions having a second anodic metal(e.g., zinc), so that they are separated (e.g., in some variationselectrically separated) and/or non-contacting, allowing preferentialrelease of one metal ion (e.g., zinc) compared to silver. This may allowcontrol of the release profile, and may extend the length of effectiverelease time for as coating.

In general, these coatings may be any appropriate thickness. Forexample, the thickness could be a few microns thick or more (e.g.,greater than 2 microns, greater than 5 microns, greater than 10 microns,greater than 15 microns), etc. For example, the thickness of the coatingmay be between about 10 microinches (approximately 2500 Angstroms orapproximately 0.25 microns) and about 25 microinches (approximately 6350Angstroms or about 0.64 microns). The thickness of the coating may beuniform or non-uniform. Only some regions of the substrate may becoated, while other regions may be masked to prevent coating. Forexample, in an electrical stimulation apparatus (e.g., cardiacstimulator, neurostimulator, etc.) the body and/or connectors of thedevice may be insulated while the electrical leads (electrical contacts)to deliver energy to the tissue may be uncoated. Alternatively in somevariations the electrical contacts are coated as described herein.

FIGS. 1A-1F conceptually describe a simple galvanic cell setup such asfor use in a body. The setup is shown treating an infection, but thesame process could be applied to healthy tissue to prevent an infection(prophylactically). The components including a first metal 2 (e.g.,silver), second metal 4 (e.g., platinum), and electrolytic fluid 6(e.g., blood) are shown individually in FIGS. 1A-1C and arranged in atissue in FIGS. 1D-1F. Electrolytic body fluid 6 is shown bathing orcontacting healthy tissue 10 as well as infected tissue 8. When silvermetal 2 contacts platinum metal 4 in body fluid 6, it forms a galvaniccell with a silver anode and platinum cathode. As shown in FIG. 1E,ionic silver 12 is generated and spreads through the body fluid, killingmicroorganisms and creating an infection-free zone 14 in body fluid 16in the vicinity of the anode. After treatment is complete, the silveranode 2 may be completely corroded 20 leaving an infection-free bodyfluid 18. Any metal with a higher redox potential than silver may beused as the cathode. The metal may be a noble metal, such as gold,palladium or platinum. Although the example shown in FIGS. 1A-1Fdescribes using a silver metal anode that is placed adjacent to aplatinum metal cathode, described herein are coatings in which theanodic metal (e.g., silver, zinc, copper) is co-deposited onto abiodegradable substrate.

In general, a coating of anodic metal and cathodic metal may beconfigured so that the anodic metal and cathodic metal are within thesame coating layer. The microregions of anodic metal may be embeddedwithin the cathodic metal, including being embedded within a matrix ofcathodic metal (or vice versa). As illustrated below, the microdomainsor microregions of anodic metal are within a cathodic matrix, allowing alarge spatial release pattern of anodic metal ions by galvanic actiontriggered by the contact of the anodic metal and the cathodic metalwithin the electrolytic bodily fluid. The coatings described herein, inwhich the anodic metal and the cathodic metal are combined as part ofthe same layer may be referred to as “combined” coatings, in which ananionic metal and a cationic metal are both jointly coated, and/ornon-homogenous (non-uniform) mixtures of anodic and cathodic metal.

The combined coatings described herein may be non-uniform mixtures ofanodic and cathodic metals. For example, the anionic metal may formmicroregions or microdomains within the cationic metal (or vice versa).In general, the cathodic metal microdomains may form one or more(typically a plurality) of continuous paths through the cathodic metal.For example, the microdomains described herein may be veins, clusters,threads, clumps, particles, etc. (including interconnected veins,clusters, threads, clumps, particles, etc.) of anodic metal, e.g.,silver, copper, and/or zinc, etc., that are connected to an outersurface of the coating, so that they are exposed to the electrolyticbodily fluid (e.g., blood). The microdomains of anodic metal may form anetwork within the matrix of the cathodic metal. Thus, the anodic metalsmay be present in one or more networks that are electrically connectedwithin the cathodic matrix. The individual sizes of particles, threads,branches, veins, etc. forming the microdomains may be small (typicallyhaving a length and/or diameter, e.g., less than a 1 mm, less than 0.1mm, less than 0.05, less than 0.01 mm, less than 0.001 mm, less than0.0001 mm, less than 0.00001 mm, etc.). Similarly, in some variationsthe matrix may be the anodic metal and the cathodic metal may bereferred to as forming microdomains (e.g., where the percentage ofcathodic metal in the coating is less than 50%, less than 45%, less than40%, less than 30%, etc. by volume of the coating).

A combined anodic metal and cathodic metal forming a combined coating(or a portion of a coating) may be formed of a single anodic metal(e.g., silver) with a single cathodic metal (e.g., platinum), which maybe referred to by the combined anodic metal and cathodic metals formingthe coating or portion of a coating (e.g., as a combined silver/platinumcoating, a combined silver/palladium coating, a combined zinc/platinumcoating, a combined zinc/palladium coating, etc.). In some variations acombined coating may include multiple anodic and/or cathodic metals. Forexample, the combined coating may include zinc and silver co-depositedwith platinum.

As mentioned, the anodic metal in the combined coating may include acontinuous path connecting the anodic metal to an exposed outer surfaceof the coating so that they can be galvanically released from thecoating. Deeper regions (veins, clusters, etc.) of the anodic metal maybe connected to more superficial regions so that as the more superficialregions are corroded away by the release of the anodic ions, the deeperregions are exposed, allowing further release. This may also exposeadditional cathodic metal. Thus, in general, anodic metal microdomainsare not completely encapsulated within the catholic metal. In somevariations, the majority of the anodic metal is not completelyencapsulated within the cathodic metal, but is connected to an exposedsite on the surface of the coating via connection through a moresuperficial region of anodic metal; although some of the anodic metalmay be completely encapsulated. For example, the coating may include ananodic metal in which less than 50 percent of the total anodic metal iscompletely encapsulated within the cathodic metal (e.g., less than 40%,less than 35%, less than 30%, less than 25%, less than 20%, less than15%, less than 10%, etc.).

The co-deposited anodic and cathodic combined coatings described hereinfor the galvanic release of anodic ions may be formed by co-depositingthe anodic metal and the cathodic metal so as to minimize the amount ofencapsulation by the cathodic material. For example, the percentage ofthe anodic material may be chosen so that there is both an optimalamount of cathodic metal to drive reasonable galvanic release in thepresence of an electrolyte, and so that there is sufficient continuityof anodic metal with the combined coating to form a continuous path toan exposed surface of the coating, making it available for galvanicrelease. For example, a coating may be formed by co-depositing theanodic metal and the cathodic metal (e.g., sputtering, vapor deposition,electroplating, etc.) where the concentration of the anodic metal ishigh enough to allow the formation of a sufficient number of continuouspaths through the thickness of the coating. We have found that acombined coating in which more than 25% by volume (or more preferablymore than 30%) of the coating is formed of the anodic metal issufficient to form a combined coating with a cathodic metal in whichmore than half (e.g., >50%) of the anodic metal is connected by acontinuous path to the surface of the coating, permitting galvanicrelease. For example, a coating having between about 33-67% of anodicmetal and between about 67-33% of cathodic metal may be preferred. Atthese percentages, less than half of the anodic metal is fullyencapsulated by the non-corroding cathodic metal and trapped within thecoating. Thus, in general, the combined coatings (also referred to asco-deposited coatings) may include more than 25% (e.g., 30% or greater,35% or greater) by volume of anodic metal that is co-deposited with thecathodic metal. In some variations, the remainder of the coating (e.g.,between 5% and 75%) may be cathodic metal. Thus, the percent of anodicmetal co-deposited with cathodic metal may be between 25%-95% (e.g.,between about 30% and about 95%, between about 30% and about 90%,between about 30% and about 80%, between about 30% and about 70%,between about 25% and 75%, between about 25% and 80%, between about 25%and 85%, between about 25% and 90%, between about 35% and 95%, betweenabout 35% and 90%, between about 35% and 85%, between about 35% and 80%,between about 35% and 75%, between about 35% and 70%, between about 35%and 65%, etc.), with the remainder of the coating being cathodic metal.Further, the coating (or at least the outer layer of the coating) may beprimarily (e.g., >95%) formed of anodic and cathodic metals distributedin the micro-domains as described herein. In some variations the coatingmay also include one or more additional materials (e.g., a metal,polymer, or the like). The additional material(s) may be inert (e.g.,not participating in the galvanic reaction between the anodic metal andthe cathodic metal), or it may be electrically conductive. For example,the additional material may be co-deposited with the anodic and cathodicmetals, and may also be distributed in a non-homogenous manner.

For example, a mixed coating may be formed using a PVD-system.Vaporization of metal components may be performed on a substrate (withor without an adhesive layer), e.g., using an arc and/or a magnetronsputter from metallic targets. Mixed coatings may be produced bysimultaneous vaporization of both metals while the substrate is heldfixed, or is moved (e.g., rotated). After coating, the coated materialsmay be cleaned, e.g., using an argon plasma and/or other methods.

As mentioned, any of the coatings described herein may be of anyappropriate thickness. For example, the coatings may be between about500 microinches and about 0.01 microinches thick, or less than about 200microinches (e.g., between about 10 microinches and about 500microinches), less than about 150 microinches, less than about 100microinches, less than about 50 microinches, etc. The thickness may beselected based on the amount and duration (and/or timing) of the releaseof anodic metal. In addition, the coatings may be patterned, e.g., sothat they are applied onto a substrate in a desired pattern, or over theentire substrate. As mentioned and described further below, differentcombined coatings may be applied to the same substrate. For example, acombined coating of silver/platinum may be applied adjacent to acombined coating of zinc/platinum, etc. The different combined coatingsmay have different properties (e.g., different anodic metal, differentanodic/cathodic metal percentages, different thicknesses, etc.) andtherefore different release profiles. Combinations in which differentcombined coatings are in (electrical) contact with each other may alsohave a different release profile than combinations in which thedifferent coatings are not in electrical contact. For example, amaterial may include a first combined coating of zinc and a cathodicmetal (e.g., zinc/platinum) and a second combined coating of silver anda cathodic metal (e.g., silver/platinum). If the first and secondcombined coatings are in electrical contact, the zinc will begalvanically released first. If the first and second combined coatingsare not in electrical contact, then both zinc and silver will beconcurrently released (though zinc may be released more quickly and mydiffuse further).

For example, FIG. 2A illustrates one example of a substrate 320 ontowhich a combined coating of anodic and cathodic metals have beenco-deposited 300. The substrate may be, for example, a bioabsorbablematerial. In some variations the substrate may be an adhesive layer,e.g., when applying the coating to some medical devices. For example, anadhesive layer may be a metal layer such as an undercoating of titaniumor tantalum. The undercoating may be of any appropriate thickness (e.g.,the same thickness or smaller than the thickness of the galvanicallyreleasing coating). In some variations the undercoating is thicker thanthe coating of the non-homogeneous mixture of anodic and cathodic metalsthat are galvanically released. Although an undercoating may be used insome variations, the coatings of anodic and cathodic metals describedherein may be coated directly onto a medical device (e.g., implant)without the need for an undercoating.

Although the combined coatings described herein may be used with anysubstrate (even non-bioabsorbable substrates), any of the examplesdescribed herein may be used with bioabsorbable substrates. In theexample of FIG. 2A the dimensions (thicknesses of the substrate andcoating) are not to scale. For example, the coating may be less than 100microinches thick. The substrate may be any thickness. In FIG. 2A,region B shows a portion of the coating and substrate, which isillustrated in the enlarged view of FIG. 2B.

In FIG. 2B, a portion of the substrate 320 (e.g. a bioabsorbablesubstrate) is shown coated with a combined coating 300. The anodicmetal, e.g., silver, 310 is shown forming veins or microregions withinthe cathodic metal 320. In this example, the silver is schematicallyillustrated as forming veins through a matrix of cathodic metal, e.g.,platinum, not shown to scale. The actual microdomains may be muchsmaller, and filamentous; for example, the microdomains may be on theorder of 10-1000 Angstroms (or more) across. FIG. 2C is anotherschematic illustration of a section through a portion of a combinedcoating on a substrate, showing microdomains of anodic metal (e.g.silver) 310, within a matrix of cathodic metal (e.g., platinum) 320. InFIGS. 2B and 2C the majority of the microdomains of anodic metal areconnected in continuous paths to the outer surface of the coating 300,allowing galvanic release of the anodic material.

FIG. 2D illustrates an example of the coating of FIG. 2C during thegalvanic release process, in which the implant including the substrateand the combined coating is place into the body, so that the coating isexposed to blood. As shown in FIG. 2D, the anodic metal (silver) in thecoating is progressively corroded as ions of silver are released intothe body to locally diffuse and provide regional antimicrobialtreatment. In this example the anodic metal (e.g., silver) 320 exposedto the surface is release, leaving a negative impression 345 in thecathodic metal 320. Regions of the cathodic metal that are left behindmay remain coated (though the substrate may also be biodegradingsimultaneous with the release of anodic metal, not shown). Typically,when the substrate is part of an implanted apparatus, the coating layeris thin enough that any remaining cathodic metal (e.g., platinum) issmall enough to be ignored or easily cleared by the body.

The combined layers are generally formed by co-depositing the anodicmetal and the cathodic metal onto the substrate. For example, a combinedlayer may be formed by simultaneously sputtering the two metals onto thesubstrate to the desired thickness. For example, both silver andplatinum may be placed into a sputtering machine and applied to thesubstrate. The amount of cathodic material and anodic material may becontrolled, e.g., controlling the percentage of the coating that ifanodic metal and the percentage that is cathodic (e.g., 30%-70%anodic/70-30% cathodic, such as 40% silver/60% platinum, etc.). Thissputtering process results in a non-uniform pattern, as discussed above,and schematically illustrated in FIGS. 2B-2C, which may be observed.Alternatively, combined layers may be formed by vacuum deposition, orany other technique that can co-deposit the two (or more) metals ontothe substrate. Formation of the coating(s) may include masking, forexample, locating coatings in particular regions of the substrate.

In general, any of the substrates (e.g., bioabsorbable substrates)described herein may be applied in a pattern, including patterns ofmultiple different combined coatings. Further, coatings may be appliedover only apportion of the substrate, which may allow more localizedrelease of the antimicrobial ions and may prevent the coating frominterfering with the properties of the substrate and/or the device thatthe substrate is part of (e.g., flexibility, surface characteristics,etc.). For example, FIGS. 3A-3C show a top view of a substrate coatedwith various combined coatings (co-deposited anodic and cathodicmetals).

For example, in FIG. 3A, the surface of the substrate 410 of an implant400 that includes alternating patterns of a first combined coating 412of silver/platinum that have been co-deposited onto the substrate and asecond combined coating 414 of zinc/platinum co-deposited onto thesubstrate. In this example the first and second coating regions areformed into strips extending along the width of the substrate; the firstand second coating regions do not overlap and are not in electricalcontact with each other. Thus, the silver ions in the first coatingregion(s) 412 will be galvanically released concurrently with the zincions galvanically released from the second coating region(s) 414 whenexposed to an electrolytic bodily fluid (e.g., blood), corroding the twolayers. FIG. 3B shows another example of a pattern of a first combinedcoating 412 (e.g., silver/platinum) and a second combined coating 414(zinc/palladium) that are arranged with alternating stripes on thesurface of the substrate 410, where the stripes are end-to-end with eachother.

FIG. 3C shows another variation of a surface 410 of an implant 400 thatincludes a pattern, shown as a checkerboard pattern, of first and secondcombined coatings. In FIG. 3C, the edges of the different coatingregions may contact each other or may be separated by a channel so thatthey are not in electrical contact for the galvanic reaction. Forexample, if the first and second regions do contact each other so thatthey are in electrical contact, then the galvanic reaction may drive therelease of the zinc ions before the release of the silver ions; once thezinc has corroded, the silver ions may be released.

In general, there may be some benefit to including multiple coatings,and in particular coatings having multiple anodic metals. Theantimicrobial region around the coated implant may be made larger andthe ions may be released over a longer time period, than with a singletype of anodic coating alone.

As mentioned, the combined coatings of co-deposited anodic and cathodicmetals could be formed in any pattern.

Other patterns that may be applied include patterns of any of thecoatings (or multiple coatings) in one or more of a sinusoidal pattern,cross-hatched pattern, a mesh pattern, a grid pattern, a web pattern, azig-zag pattern, etc. Patterns may be formed by masking during theapplication (e.g., vapor deposition) process. For example, FIGS. 24A-24Cillustrate patterns of the coatings described herein that may beparticularly useful. For example, in FIG. 24A, a cross-hatched patternis shown. These patterns may be formed on any appropriate substrate,including on catheters, tubing, and other apparatuses. In particular,these patterns may be applied to flexible and/or bendablesurfaces/substrates. FIG. 24B shows a coating pattern that may beformed, e.g., on a catheter or tube and has a diagonal-hatched pattern.These patterns may allow flexibility and still provide antimicrobialcoverage. In some variations the patterns (e.g., mesh, web, etc.patterns) may include regular gaps or openings exposing the baresurface/substrate; these gaps may be a maximum size, for example, lessthan 2 mm (e.g., less than 1.5 mm, less than 1.0 mm, less than 0.9 mm,less than 0.8 mm, less than 0.7 mm, less than 0.6 mm, less than 0.5 mm,etc.) in diameter.

FIG. 24C illustrates one example of a sinusoidal pattern of a coatingapplied to a surface of an apparatus.

Bioabsorbable Substrates

In some variations, the substrate is bioabsorbable and/or biodegradable.For example, the substrate may be formed as a flexible filament, and thecoating of anodic and cathodic metals that may corrode to release anodicions may allow the flexible filament to remain flexible. Galvanicrelease results in degradation (e.g., corrosion) of the coating.

The substrate onto which the combined coatings may be applied may be anyappropriate substrate, and in particular, may be a bioabsorbablesubstrate. Examples of bioabsorbable materials that may be used includespolymeric materials such as: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL), and combinations of these.

In general, bioabsorbable materials for medical applications are wellknown, and include bioabsorbable polymers made from a variety ofbioabsorbable resins; for example, U.S. Pat. No. 5,423,859 to Koyfman etal., lists exemplary bioabsorbable or biodegradable resins from whichbioabsorbable materials for medical devices may be made. Bioabsorbablematerials extend to synthetic bioabsorbable or naturally derivedpolymers.

For example, bioabsorbable substrates may include polyester orpolylactone selected from the group comprising polymers of polyglycolicacid, glycolide, lactic acid, lactide, dioxanone, trimethylenecarbonate, polyanhydrides, polyesteramides, polyortheoesters,polyphosphazenes, and copolymers of these and related polymers ormonomers. Other bioabsorbable substrates may include substrates formedof proteins (e.g., selected from the group comprising albumin, fibrin,collagen, or elastin), as well as polysaccharides (e.g., selected fromthe group comprising chitosan, alginates, or hyaluronic acid), andbiosynthetic polymers, such as 3-hydroxybutyrate polymers.

The bioabsorbable substrate may be absorbed over a predetermined timeperiod after insertion into a body. For example, the bioabsorbablesubstrate may be absorbed over hours, days, weeks, months, or years. Thesubstrate may be bioabsorbed before, during or after release of theanodic metal ions from the combined coating. In some variations therelease of the antimicrobial ions is timed to match thedegradation/absorption of the substrate. Further, the absorption of thesubstrate may facilitate the release of the anodic metal ions. Forexample, some of the bioabsorbable substrates described herein mayresult in a local pH change as the substrate is bioabsorbed; the releaseof the metal ions may be facilitated by the altered pH.

FIG. 4 shows an example of a pouch device formed from woven lengths ofbioabsorbable filament that is flexible. The filament is formed of abioabsorbable polymer, PGLA, and this bioabsorbable substrate has beencoated with the combined anodic metal/cathodic metal coating describedabove. In FIG. 4A, the pouch of PGLA fibers coated with (e.g., by vapordeposition) co-deposited silver and platinum galvanically releasessilver ions after insertion into the body. The release of anodic metalions (e.g., silver ions) is enhanced as the bioabsorbable substrate(e.g., PGLA) is hydrolyzed. Hydrolysis lowers the local pH and this mayincrease solubility of silver and bio-absorption.

The pouch of FIG. 4 may be used similarly to those described in U.S.Pat. No. 8,591,531, herein incorporated by reference in its entirety.

In general, the bioabsorbable substrate may be formed into anyappropriate shape or structure. For example, a bioabsorbable substratemay be a filament that is coated, completely or partially, by one ormore of any of the combined coatings of anodic and cathodic metalsco-deposited onto the bioabsorbable substrate. Coated strands (e.g.,filaments, strings, wires, etc.) of bioabsorbable substrate may be usedby themselves, e.g., as suture, ties, etc. within a body, or they may beused to form 2D or 3D implants, for example, by weaving them. Thecombined coatings described herein may be coated onto these structureseither before or after they have been formed. For example, a coatedfilament may be woven into a net (or into a pouch for holding animplantable device, as shown in FIG. 4), or the filament may be woveninto a net and then coated.

FIG. 5A shows an example of a filament that may be formed of abioabsorbable substrate that is coated with a combined anodic/cathodicmetal coating for galvanic release of anodic metal ions. In FIG. 5A, thefiber 500 may include uncoated regions 505 alternating with coatedregions 503. The coated region(s) may be a spiral shape around thefiber, a ring around the fiber (as shown in FIG. 5) or any otherpattern. Multiple coatings may be used (see, e.g., FIGS. 3A-3C). Thecoated fiber may retain its flexibility. In some variations the fibermay be used, e.g., as a suture.

FIGS. 5B-5D and 6 illustrate different variations of sutures that may becoated as described herein. Note that although some of these substratesforming the suture are bioabsorbable, they do not need to be. In somevariations, the suture material (the substrate onto which thegalvanically releasable coating is applied) is not biodegradable orbioabsorbable. Any variation of suture material may be used. Forexample, the suture material may be a barbed suture, as shown in FIG.5B. The barbed suture 560 may be coated 565 or otherwise treated toinclude the co-deposited coating of anodic metal (e.g., 40% by volume ofsilver) and cathodic metal (e.g., 50% by volume of platinum) arrangedwith continuous microdomains of the anodic (and/or cathodic) metalextending from the outer side of the outer surface of the coatingthrough the thickness of the coating. An entire length of suture 580 maybe coated 585, as shown schematically in FIG. 5C, or just a portion ofthe suture. The thickness of the coating may be below a threshold, whichmay help maintain the flexibility of the suture material. For example,the thickness may be between 10 microinches and 50 microinches. FIG. 5Dillustrates a suture kit including a length of suture 580 and a needle591; either or both the suture 580 and needle 591 may be coated. Thesame or different anodic metal and/or cathodic metal may be used on theneedle as the thread. For example, the needle may include the morequickly releasing nickel as the anode, while the thread, which resideslonger in the body, may use and anodic metal of silver.

FIG. 6 shows another example of a suture 600 that is coated 620 over thedistal portion of the suture, which may be used in the body. The suturemay be pre-loaded on a device (including an implant, needle, etc.). Thesuture may be formed of a bioabsorbable substrate 610 onto which thecoating is applied.

In any of the devices described herein, the coating may be made directlyonto the substrate. In some variations the coating may be made on top ofanother coating (e.g., a primer coating) which may be made to preparethe substrate for the coating. Examples of primer coatings are adhesioncoatings. An example of a primer coating may include titanium and/ortantalum undercoatings, as described above.

Additional examples of woven structures are shown in FIGS. 7-11. In FIG.7, the device 700 is formed of filaments 710 woven or arranged into amesh (shown in the enlarged view 720) that are coated with a combinedcoating (or multiple types of combined coatings) as described herein. Inthis example, the mesh formed is configured as a transvaginal mesh(intravaginal mesh) that may be used for the treatment of vaginalprolapse, for example. Slings or other anatomical support structures,either durable or biodegradable, could also be formed. These devices maygalvanically release one or more type of anionic metal ion havingantimicrobial effect. For example the mesh may be coated with a coatingof silver/platinum that is co-deposited onto the mesh or the fibersforming the mesh for galvanic release of silver from the coating.

FIGS. 8A and 8B illustrate another example of a structure, shown as awoven structure, that may also be configured as a non-woven (e.g.,solid) structure. In FIG. 8A the device 400 is a patch or plug that maybe used for treating a hernia. In this example, the patch is a wovenmesh that includes two types of combined coatings: silver/platinum andzinc/platinum in different regions over the surface of the patch. Darkerregions 803 may indicate the silver/platinum co-deposited coatingregions, while the lighter regions 805 represent co-depositedzinc/platinum regions. The entire patch outer surface or only a portionof the outer surface may be coated; in FIG. 8A, only discrete regionsare shown as coated, for the sake of simplicity. FIG. 8B shows anenlarged view illustrating the fibers forming the weave of the patch. Asshown in FIG. 8B, only some of the fibers are coated (e.g., every otherfiber of the warp); in some variations, alternating fibers in onedirection (warp) are coated with different anodic/cathodic metals, whilefibers in the opposite direction (weft) are uncoated.

FIG. 9 illustrates another example of a woven material, formed of abioabsorbable fiber, coated with the combined coatings described hereinfor galvanic release of antimicrobial metal ions. In FIG. 9, the deviceis a patch that could be used, e.g., within the knee after surgery, toreduce the chance of infection. In this example, as in FIGS. 8A and 8Babove, the patch may include filaments/fibers having different coatings(e.g., silver/platinum, zinc platinum, silver palladium, zinc palladium,etc.) and/or different regions on the patch, as shown by the light anddarker regions in FIG. 9. In some variations the patch may be wornoutside of the body, e.g., it is “implanted” by placing it over a wound,rather than entirely within the body. Blood in the wound region may actas the electrolytic fluid, allowing galvanic release of the metal ions.

Similarly, FIG. 10 illustrates a dural replacement mesh 810 that may beimplanted into a subject's head 812 to replace dural matter followingtrauma and/or surgery. The mesh may be formed of a non-bioabsorbablematerial (or a bioabsorbable material) that is coated as described aboveso as to galvanically release antimicrobial metal ions.

FIG. 11 illustrates another example of a fabric or mesh that may beimplanted into a patient as part of a surgical procedure. In FIG. 11,the mesh is a woven fabric that has been coated with one or morecombined coatings of anodic and cathodic metals co-deposited on thesubstrate (e.g., bioabsorbable substrate) for galvanic release of metalions. The material may be used, for example, as part of a large jointprocedure such as knee replacement, or spinal surgery (e.g., fixationusing rods, screws, etc.) in place of currently used antibiotic powers.For example the coated bioabsorbable mesh could be in, around, or overthe surgical site and used to galvanically release antimicrobial ionsfollowing surgery. The implant (material) would break down over time,and be absorbed following implantation (e.g., within 30 days followingthe procedure), allowing sufficient time for the patient to recover andavoid infection potentially introduced by the procedure and/or theresulting wound.

Although the devices described herein include flexible, e.g., filamentor mesh, structures, the devices may also be configured as rigid or moretraditional surgical implants, including screws, rods, staples,cannulas, etc. The substrate may be bioabsorbable.

For example, FIGS. 12A-12B shows one variation of a cannula that may beused within a body and galvanically release antimicrobial metal ions. InFIG. 12A, the cannula 300 includes a substrate 320 onto which a combinedcoating 330 is applied in a spiral pattern. The combined coatinggalvanically releases anodic metal ions (e.g., silver, zinc, copper), isincludes the anodic metal that has been co-deposited with cathodic metal(e.g., platinum, palladium, etc.). In this example, the inner surface310 of the cannula 300 may also be separately coated with a combinedcoating (the same or a different coating). FIG. 12B shows a side view ofthe catheter of FIG. 12A.

Any of the devices described herein may be used as part of a surgicalprocedure within a body (e.g., human, animal, etc.). In general, thecombined coatings described herein may be implanted into the body andmay galvanically release metal ions over an extended period of time(e.g., days, weeks, months). For example, in some variations the coatingand/or apparatus (e.g., device) may be configured to galvanicallyrelease metal ions for 30 days, 60 days, 90 days, or more.

The anti-microbial coatings, devices and systems described herein mayuse two or more types of metal ions with anti-microbial properties, suchas silver and zinc. The zone of inhibition of microbial activity/growthformed around the coated devices due to the released metal ions may beenhanced where two different types (e.g., silver and zinc) are released.The combination of zinc and silver has been observed to have asynergistic effect compared to either metal alone.

Further, when the combined coatings described herein are used incombination with a bioabsorbable (e.g., biodegradable) substrates ormaterial, the metal ions may form complexes with the byproducts ofdegradation of the substrate (e.g., polymeric substrates including PLA,PLGA, PGA) such as lactate, galactate, or glucoate. These substrates mayincrease the anti-microbial activity. For example, the range ofdiffusion of the anionic metal ions (e.g., zinc, silver, etc.) may beincreased by the creation of a complex between the metal ions and thepolymeric degradation byproduct. Further, as mentioned above,degradation of the polymers may create acidic byproducts such as lacticacid, galactic acid, and/or glycolic acid. The drop in pH and formationof the anionic byproducts may further enhance the rate of the galvanicreaction.

Thus, the apparatuses and methods above may, in some variations,generally take advantage of the use of bioabsorbable substrates that arecoated through a co-deposition process of a cathodic metal (e.g.,platinum, palladium, gold, etc.) and an anodic metal (e.g., silver,zinc, copper) to form a galvanic circuit in a fluid (e.g., electrolytic)medium to create an antimicrobial zone. The degradation of thebioabsorbable substrate may further enhance this antimicrobial zone,e.g., by forming complexes with the released metal ions to furtherdiffuse the ions as well as to alter the local pH to enhance thegalvanic reaction. In general, as described above, the combined coatingsdescribed herein can be quite thin and do not compromise theflexibility, chemic structure, strength (e.g., tensile strength) orchemical properties of the underlying substrate(s).

EXAMPLES

Any of the coatings described herein may be included on all or a portionof a medical device. For example, any of the following devices may bewholly or partially coated with a mixture of an anodic metal and acathodic metal as described herein: shunts (e.g., drainage shunts,dialysis shunts, etc.), catheters (e.g., urinary catheters,intravascular catheters, etc.), ports (e.g., portacath, etc.),artificial joints (e.g., total hip, knee, etc.), pacemakers,defibrillators (ICD), pain management implants, neuro-stimulators,neuro-pacemakers, stents, bariatric balloons, artificial heart valves,orthodontic braces, pumps (drug pumps, e.g., insulin pumps, etc.),implantable birth control devices, IUDs, etc.

Any of the coatings described herein may be included on all or a portionof a medical tool. For example, any of the following materials for usein operating on a subject may be wholly or partially coated with amixture of an anodic metal and a cathodic metal as described herein:surgical gauze, surgical sponges, wound packing materials, augmentationand/or cosmetic implants (e.g., breast/chin/facial implants), surgicalretractors, needles, clamps, forceps, and the like.

For example, FIG. 13B illustrates one example of an implant that may becoated on an outer surface with any of the antimicrobial coatingscomprising a non-homogeneous mixture of anodic and cathodic metals forgalvanic release of anti-microbial ions, as described herein, andimplant as illustrated in FIG. 13A. In this example all or just aportion of a pacemaker 1301 may be coated on an outer surface with themixture of between about 30% and 70% by volume of an anodic metal, andbetween about 30% to 70% by volume of a cathodic metal. The anodic andcathodic metals may be co-deposited on the outer substrate surface toform a non-uniform mixture of the anodic and cathodic metals, whereinthe coating comprises a plurality of microregions or microdomains ofanodic metal in a matrix of cathodic metal or a plurality ofmicroregions or microdomains of cathodic metal in a matrix of anodicmetal. In some variations different regions may be coated with differentanodic metals (e.g., forming a pattern of silver, nickel, etc. releasingregions). In some variations the electrical leads (e.g., an outersurface of the leads that are tunneled through the body, as illustratedin FIG. 13A) may be coated as described herein. Similarly, electricalleads for other devices (e.g., neurostimulators) may be coated asdescribed herein. In general, these coatings may terminate before theelectrically active regions of the lead.

For example, FIG. 13C shows a schematic depiction of an implantablepacemaker (defibrillator) system 1300 including electrodes implanted inthe heart H of a subject (patient). A cardiac stimulation anddefibrillation device 1310 is connected to the heart H via an electrodelead 1320 which comprises three lead branches or electrode supply leads1330, 1340 and 1350. Each lead branch comprises sensing or stimulationelectrodes (which are not depicted individually) on or near the distalend thereof, and lead branch 1350 also comprises an elongateddefibrillation electrode 1360. In the arrangement shown, lead branch1330 is placed in the right atrium, lead branch 1340 is placed in theleft atrium of the heart H, and lead branch 1350 on which defibrillationelectrode 1360 is installed is placed in the right ventricle (RV). Asmentioned above, any of the leads described herein may be coated withthe mixture of between about 25% to 75% (e.g., 30% and 70%) by volume ofan anodic metal, and a cathodic metal that are co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals. The coatings may include the electrical contacts (notshown) or the contacts may not be coated. Different coatings may be used(e.g., different anodic and/or cathodic metals, different patterns ofcoating, etc.) may be used. In general, the coating comprises aplurality of microregions or microdomains of anodic metal in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal. This coating may be made onthe leads without detrimentally affecting the flexibility of the leads.For example, the coating may be applied thin enough to allow the lead tobend easily, while still providing sufficient elution of antimicrobialmetal ions (e.g., silver ions) over a long time period (of weeks andmonths).

FIGS. 14A and 14B, as well as FIGS. 15A and 15B illustrate anothervariation of a type of device, a catheter such as a Venus catheter thatmay be partially or completely coated as described herein. The coatingsdescribed herein may benefit virtually any type of catheter; a Venuscatheter is generally a tube inserted into a vein in the neck (as shownin FIG. 14A), chest, or leg, e.g., near the groin, usually only forshort-term hemodialysis. In FIG. 14A, the tube splits in two after thetube exits the body. The two tubes have caps designed to connect to theline that carries blood to the dialyzer and the line that carries bloodfrom the dialyzer back to the body. A person must close the clamps oneach line when connecting and disconnecting the catheter from the tubes.Any portion (or the entire device) may be coated as described herein.For example, in FIGS. 14A and 14B, the outer surface of the catheter1405 and/or the Venus and arterial lines may be coated as describedherein.

In some devices, it may be helpful to provide a cuff or cuffs on thedevice that are specifically configured for the galvanic release ofantimicrobial ions. For example, FIGS. 15A and 15B illustrate catheters1500, 1501 for long-term vascular access that includes a cuff that maybe at least partially coated as described herein for the release ofantimicrobial ions. Adjacent to the ion-releasing cuff 1505 is atissue-ingrowth cuff 1507.

In general, the wide use of invasive medical devices, includingintravascular catheters has led to an increase in infections related tothe use of the medical device. However, intravascular catheters areoften associated with serious infectious complications, such ascatheter-related bloodstream infection (CRBSI). In fact, CRBSI isconsidered to be the most common type of nosocomial bloodstreaminfection, a finding that has been attributed to the wide use ofintravascular catheters in hospitalized patients. It is estimated that 7million central venous catheters (CVCs) will be inserted annually in theUnited States. Even with the best available aseptic techniques beingused during insertion and maintenance of the catheter, 1 of every 20CVCs inserted will be associated with at least 1 episode of bloodstreaminfection.

In the early 2000's, an estimated 300,000 cases of catheter-relatedbloodstream infection (CRBSI) occurred in the United States each year.Existing interventions to control CRBSI includeanticoagulant/antimicrobial lock, use of ionic silver at the insertionsite, employment of an aseptic hub model, and antimicrobial impregnationof catheters. However, these solutions have not proven ideal.

Several factors pertaining to the pathogenesis of CRBSI have beenidentified during the last decade. The skin and the hub are the mostcommon sources of colonization of percutaneous vascular catheters. Forshort-term, nontunneled, noncuffed catheters, the organisms migrate fromthe skin insertion site along the intercutaneous segment, eventuallyreaching the intravascular segment or the tip. Thus, it may bebeneficial to include the galvanic release coating(s) described hereinalong any (or all) portions of the catheters that are inserted into thepatient, to allow galvanic release of the antimicrobial ions (e.g.,silver, nickel, etc.) as described above. For example, FIG. 16illustrates one variation of a catheter 1601 (shown as an intravascularcatheter in this example) that has been coated along its length (or overa region) with a layer of the mixture of between about 25% to about 75%(e.g., 30% and 70%) by volume of an anodic metal, and between about 25%to about 75% (e.g., 30% to 70%) by volume of a cathodic metalco-deposited on an outer substrate surface to form a non-uniform mixtureof the anodic and cathodic metals. The coating may comprise a pluralityof microregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal. The anodic metal is galvanically releasedas antimicrobial ions when the apparatus is inserted into a subject'sbody.

Generally, long-term catheters (particularly those that are cuffed orsurgically implanted, such as those illustrated in FIGS. 15A-15B), thehub is a major source of colonization of the catheter lumen, whichultimately leads to bloodstream infections through luminal colonizationof the intravascular segment. Thus, in some variations the hub regionmay be coated as described herein.

In addition to the examples described above, other insertable orimplantable device that may be coated as described herein may includeimplantable devices such as drug delivery devices (e.g., pumps), cardiacmanagement devices (e.g., pacemakers), cochlear implants, analytesensing devices, catheters, cannulas or the like. Essentially anymedical device which experiences microbial colonization and/or biofilmformation and/or encrustation is appropriate for the practice of thepresent invention, including analyte sensing devices such aselectrochemical glucose sensors, drug delivery devices such as insulinpumps, devices which augment hearing such as cochlear implants, urinecontacting devices (for example, urethral stents, urinary catheters),blood contacting devices (including needles, blood bags, cardiovascularstents, venous access devices, valves, vascular grafts, hemodialysis andbiliary stents), and body tissue and tissue fluid contacting devices(including biosensors, implants and artificial organs). Medical devicesinclude but are not limited to permanent catheters, (e.g., centralvenous catheters, dialysis catheters, long-term tunneled central venouscatheters, short-term central venous catheters, peripherally insertedcentral catheters, peripheral venous catheters, pulmonary arterySwan-Ganz catheters, urinary catheters, and peritoneal catheters),long-term urinary devices, tissue bonding urinary devices, vasculargrafts, vascular catheter ports, wound drain tubes, ventricularcatheters, hydrocephalus shunts, cerebral and spinal shunts, heartvalves, heart assist devices (e.g., left ventricular assist devices),pacemaker capsules, incontinence devices, penile implants, small ortemporary joint replacements, urinary dilator, cannulae, elastomers,hydrogels, surgical instruments, dental instruments, tubings, such asintravenous tubes, breathing tubes, dental water lines, dental draintubes, and feeding tubes, fabrics, paper, indicator strips (e.g., paperindicator strips or plastic indicator strips), adhesives (e.g., hydrogeladhesives, hot-melt adhesives, or solvent-based adhesives), bandages,orthopedic implants, and any other device used in the medical field.Medical devices also include any device which may be inserted orimplanted into a human being or other animal, or placed at the insertionor implantation site such as the skin near the insertion or implantationsite, and which include at least one surface which is susceptible tocolonization by biofilm embedded microorganisms. Medical devices alsoinclude any other surface which may be desired or necessary to preventbiofilm embedded microorganisms from growing or proliferating on atleast one surface of the medical device, or to remove or clean biofilmembedded microorganisms from the at least one surface of the medicaldevice, such as the surfaces of equipment in operating rooms, emergencyrooms, hospital rooms, clinics, and bathrooms. Non-implanted devices foruse in a medical procedure that may be coated as described hereininclude surgical tools, e.g., suturing devices, forceps, retractors,sponges, etc.

Orthopedic devices may in particular benefit from the coatings describedherein. An implant as described herein may be used to treat bone and/orsoft tissue. In some variations the implants are bone implantsspecifically, and may be configured to support as well as treat thebone. For example, the implant may be used to secure (as a screw, nail,bolt, clamp, etc.) another member such as a plate, rod, or the like, orthe implant may itself include a support member such as a rod, plate,etc. In some variations, the implant is a soft tissue implant that isconfigured to be secured within non-bone body structures.

For example, FIGS. 17A-17C illustrate one variation of an apparatus foruse in delivering an antimicrobial ion (e.g., silver ions) to a repairsite to prevent or treat infection. In this example, apparatus includesa replaceable/removable insert that is coated. The insert maybe a meshor other material having a relatively large surface to volume ratio(e.g., large surface area). For example, FIG. 17A shows a cannulatedbone screw 1701, e.g., a bone screw having a central cannula region (notvisible in FIG. 17A) into which another device or element may beinserted, such as the bioabsorbable material 1703 (mesh) shown in FIG.17B. In FIG. 17A, the bone screw includes a distal threaded region 1705and a more proximal head 1707. In FIG. 17B the bioabsorbable mesh 1703is coated with the antimicrobial ion releasing coating such as describedherein (e.g., 30% silver/70% platinum) to a thickness of 100microinches. The cannulated bone screw 1701 may also be coated, or maynot be coated. Either before or after inserting the bone screw into thebody, the bioabsorbable insert 1703 may be inserted into the cannula ofthe bone screw 1701. This is illustrated in FIG. 17C. In practice,multiple inserts 1703 may be added to the bone screw device.

In some variations, the bone screw may itself be coated, without the useof an additional element (e.g., a bioabsorbable insert). FIGS. 18A and18B illustrate different variations of implants (e.g., bone screw) thatinclude antimicrobial ion releasing coatings as described herein. InFIG. 18A, the entire bone screw 1801 is coated with an antimicrobial ionreleasing coating comprising a mixture of between about 25% to 75%(e.g., 30% and 70%) by volume of an anodic metal, and between about 25%to 75% (e.g., 30% to 70%) by volume of a cathodic metal co-deposited onthe outer substrate surface to form a non-uniform mixture of the anodicand cathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate). In FIG. 18B, the bone screw apparatus is a screw that hasnot been completely coated, but includes differently coated regions, orregions that are both coated and uncoated. In this example the substrateis the surface of a bone screw having a striated pattern of regions ofcoatings alternating with uncoated regions.

FIGS. 19A-19B illustrate another variation in which the implant isconfigured as an orthopedic device (e.g., bone screw) having extendablemembers that can be extended out of the body of the bone screw toproject into the tissue and allow release of antimicrobial ions into thesurrounding tissue. In this variation, the implant 1901 is configured asa bone screw that is hollow or contains a hollow inner body region (notvisible in FIG. 19A) into which a replaceable/rechargeable treatmentcartridge may be inserted and/or removed. The cartridge may be itselfscrewed into the body, or it may be otherwise secured within the body.The cartridge may include one or more (e.g., a plurality) of ion releasemembers 1909 extending or extendable from the cartridge and thereforethe implant. The ion release member(s) may be configured to releasesilver, zinc or silver and zinc and may be coated with any of thecoatings described herein. In general, an ion release member may beconfigured as an elongate member such as an arm, wire, branch, or thelike. The ion release member may be a coated member such as a Nitinol orother shape-memory member coated with an antimicrobial ion releasingcoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate). As mentioned, the implant (or thetreatment cartridge portion) may include a plurality of ion releasemembers.

These implants may have one or more exit channels 1905. In general theexit channels may be openings from the inner hollow region (e.g.cannulated body) of the implant through a side wall of the implant andout, possibly in the threaded region 1907. Thus, in FIGS. 19A and 19B,the exit channel is configured to deflect the one or more ion releasemembers away from a long axis of the implant. For example, the exitchannel may be configured to deflect the one or more ion release membersagainst a thread of the outer threaded region so that it deflects awayfrom the implant. In some variations a plurality of exit channelsextending through the cannulated body 1903.

An implant such as the one shown in FIGS. 19A-19B may also include aguide (or guide element, including a rail, keying, etc.) within thechannel configured to guide or direct the one or more ion release memberout of the cannulated body 1903 from the at least one exit channel 1905.The exit channels may be configured to allow tissue (e.g., bone)ingrowth, which may help with stability of the device once implanted.For example, the exit channels may be slightly oversized compared to theion release members, permitting or encouraging in-growth. In somevariations the exit channels may be doped or otherwise include atissue-growth enhancing or encouraging factor (such as a growth factor),or may be otherwise modified to encourage tissue growth.

A treatment cartridge may be replaceable. For example, a treatmentcartridge may be configured to be removable from the cannulated body ofthe implant in situ, without removing the body of the implant from thedevice. Thus, the body of the implant may be structurally supportive(e.g., supporting the bone) while the silver-releasing cartridge armsmay be re-charged by inserting another (replacement) cartridge after theprevious cartridge has corroded. For example, an elongate cannulatedbody 1903 may be configured as bone screw (e.g., an intramedullary bonescrew).

In addition, the antimicrobial coatings described herein may also beeffective for use in non-implantable and/or insertable devices. Asmentioned above, any apparatus that may come into contact with aconductive (e.g., electrolytic) fluid, such as bodily fluids, maybenefited from the antimicrobial coatings described herein; suchapparatuses are not limited to medical devices and systems.

For example, also descried herein are garments (e.g., gloves, masks,scrubs), including facial masks (surgical masks, filters, or the like),sporting equipment (e.g., facemasks, mouthpieces, helmets, etc.), shoes(sole/shoe inserts, etc.), jewelry (necklaces, bracelets, rings, etc.)and the like, that may be coated or may include a coated region, whereinthe coating comprises any of the antimicrobial ion releasing coatingsdescribed herein, such as a coating comprising a mixture of betweenabout 25% to about 75% (e.g., 30% and 70%) by volume of an anodic metal(e.g., silver), and between about 25% to about 75% (e.g., 30% to 70%) byvolume of a cathodic metal (e.g., platinum) co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate).

FIG. 20 is one example of a non-medical application of a coating asdescribed herein. For example, an animal cage 2005 may be coated(particularly on the bottom region) with any of the antimicrobialcoatings described herein. In this example, the cage may include anantimicrobial ion releasing coatings as described herein, such as acoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate).

Similarly, any household apparatus that may be exposed to a bodily fluid(including sweat and/or mucus, as from sneezing or coughing) may becoated with any of the coatings described herein, to act as an effectiveantimicrobial barrier. For example, FIG. 21 illustrates a doorknob 2101that may be partially or completely coated with any of the antimicrobialion releasing coatings described herein on a portion that will be heldby an operator's hand 2109. Thus, this region may be coated with acoating comprising an antimicrobial ion releasing coating such as acoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate). Other household fixtures that may bereadily coated include light switches, door handles/pulls, kitchenappliances (and particularly handles/controls for kitchen appliances),tabletop and/or countertop surfaces, and bathroom surfaces. For example,a toilet handle, toilet (including toilet seat and/or bowl), sink,and/or faucet may be coated as described herein.

In addition, cookware, dining wear, and/or cutlery may be coated. Suchcoatings are safe, and non-toxic, though still antimicrobial, and may beextremely long lasting (e.g., extending over months or years, dependingon coating thicknesses and use). Further, these coatings do not degradeor lose their antimicrobial activity, which is dependent primarily orexclusively on the galvanic release of ions (e.g., silver ions). Forexample, as shown in FIGS. 22A-22B, cutlery (e.g., spoons 2205, forks2207, etc.) may be coated as described herein, particularly on theportions to be placed in a user's mouth. FIG. 22B shows an example of aninfant spoon 2205′ having an elongate handle and end region 2230 formingthe spoon that is to be placed in an infant's mouth; this end region2230 may be coated specifically, e.g., with an antimicrobial ionreleasing coating as described herein, such as a coating comprising amixture of between about 25% to about 75% (e.g., 30% and 70%) by volumeof an anodic metal (e.g., silver), and between about 25% to about 75%(e.g., 30% to 70%) by volume of a cathodic metal (e.g., platinum)co-deposited on the outer substrate surface to form a non-uniformmixture of the anodic and cathodic metals, wherein the coating comprisesa plurality of microregions or microdomains of anodic metal in a matrixof cathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal, the microregions ormicrodomains forming a continuous path of interconnected veins of anodicmetal through the coating thickness, or a continuous path ofinterconnected veins of cathodic metal through the coating thickness,wherein the continuous path extends from an outer surface of the coatingto the substrate to the opposite side of the coating (which may beadjacent to the substrate). The substrate may be stainless steel,polymer, or any other appropriate material. The coating is both washableand sterilizable without losing efficacy.

In some variations, the substrate is a particle, such as a micro (ornano) particle that is coated as described herein, to form a powder orother material that may be added to a device or system to provideantimicrobial activity. For example, polymeric particles may be coated(or a polymeric material may be coated and ground/broken up into smallerparticles) with any of the antimicrobial ion releasing coatingsdescribed herein, such as a coating comprising a mixture of betweenabout 25% to about 75% (e.g., 30% and 70%) by volume of an anodic metal(e.g., silver), and between about 25% to about 75% (e.g., 30% to 70%) byvolume of a cathodic metal (e.g., platinum) co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate). The resulting particles (which may be referred to as anantimicrobial powder) may be added, e.g., into structures or ontosurfaces that will come into contact with bodily fluids.

Surface Treatments

As mentioned above, the antimicrobial coatings described herein may beapplied directly to any appropriate substrate; the substrate may, insome variations, form a part of another device or system that comes intocontact with a bodily fluid and therefore benefits from the use of theseantimicrobial coatings. For example, a coating may be made directly ontothe substrate, or it may be made onto another coating (e.g., a primercoating) which may be made to prepare the substrate for the coating.Examples of primer coatings are adhesion coatings, which may include atitanium and/or tantalum undercoating, as described above.

In some variations, the material is pretreated to prepare the surface toreceive the coating. For example, in some metals (e.g., nickel titanium,stainless steel, etc.) the surface may oxidize naturally, and it may bebeneficial to remove this oxide layer prior to applying theantimicrobial coatings described herein. For example, a substrate may beprepared by removing an oxide layer (or for other reasons) by vacuumblast cleaning with a noble gas such as argon (e.g., argon blasting orargon blast cleaning under a vacuum). Removing the thin outer oxidelayer may enhance adhesion of the coating. In general, vacuum cleaningmay be helpful, and may be performed immediately before applying thecoating (e.g., co-sputtering the anodic and cathodic materials).

Other useful pre-treatments may include applying an undercoating layer(e.g., of platinum, parylene, etc.). Such undercoatings may be appliedfirst (e.g., by sputter deposition, etc.).

One additional benefit of the coatings described herein is that they maybe applied in a relatively cool application process, e.g., in which thetemperature at which the co-deposition of the anodic material andcathodic material is applies is relatively cool (e.g., less than 150°C., less than 120° C., less than 100° C., less than 90° C., less than80° C., less than 70° C., less than 60° C., less than 50° C., etc.). Thetemperature of application may be adjusted along with the time to formthe coating (e.g., cooler application may generally take longer). Coolerapplication may be particularly beneficial when the substrates to whichit is being applied is temperature sensitive, or when it is beingapplied to a device (including devices having active/electronic parts)that are rate below a predetermined temperature.

Post-Coating Treatments

Any of the apparatuses described herein (e.g., any of the coatingsdescribed herein) maybe treated to enhance the galvanic release ofantimicrobial ions (e.g., silver). Such treatments may be referred to aspost-coating treatments because they may be performed after the coatinghas been applied. For example, any of the apparatuses described hereinmay include coatings that are treated to enhance the surface area bycracking, fracturing, or otherwise roughening the coating, which mayincrease the exposed surface area of the coating.

Post-coating treatments may include thermal treatments (e.g., exposingthe surface to a cooler temperature to crack or fracture the coating),and/or energy (e.g., ultrasound, RF, etc.) to fracture the surface. Forexample, in some variations the coating may be connected to anoscillating high voltage source that makes cracks in the coating. Forexample, FIGS. 23A and 23B illustrates a variation of a substrate 2320(similar to the example shown in FIGS. 2A-2D) has been coated with anantimicrobial ion releasing coating 2300 as described above. In thisexample, after co-depositing the anodic and cathodic metals, the coatedapparatus has been treated to fracture the coating, formingbreaks/fractures 2350 (shown schematically in FIG. 23B from the enlargedregion B in FIG. 23A). In this example, the fractures 2350 are formedvertically into the coating to expose more of the anodic metal andcathodic metal, potentially allowing for greater (and/or faster) releaseof anodic antimicrobial ions.

Thus, in any of the apparatuses described herein, the coatings may befractured (cracked, etc.) to enlarge the surface area. Cracks orfractures may be formed of a predetermined density and/or depth. Forexample, the coating may be fractured or may include cleavage regionsinto the thickness of the coating at a density of between 0.01% and 80%of the surface (e.g., greater than 0.1%, greater than 1%, greater than5%, greater than 10%, greater than 15%, etc.). The percentage offracturing typically results in an increase the in the surface area, andmay therefore be referred to as a percentage increase in the surfacearea. For example the percent increase in the surface area due tofracturing the surface may result in an increase of greater than 0.25times the un-fractured surface area (e.g., a 25% or greater surface areafollowing fracturing). In some variations the surface area may beincreased greater than 0.3 times (e.g., 0.35× or greater. 0.40× orgreater, 0.45× or greater, 0.5× or greater, 0.6× or greater, 0.75× orgreater, 0.8× or greater, 0.9× or greater, 1× or greater, 2× or greater,3× or greater, etc.).

As mentioned above, in general, the antimicrobial coatings describedherein may be included on any appropriate surface, including medicaldevices (e.g., implants, surgical tools, medical clothing, gloves,surgical drapes, covers, etc.), and the like. For example, FIGS. 25A-25Billustrate an endoscope 2503 having a protective (sterile) drape 2501that may be used as part of a surgical procedure to maintain a sterilefield. In FIGS. 25A and 25B, the drape 2501 may be coated completely orpartially on a surface (e.g., outer surface) with any of the coatings asdescribed herein. For example, the flexible drape outer surface may becoated with a coating comprising a mixture of between about 25% to about75% (e.g., 30% and 70%) by volume of an anodic metal (e.g., silver), andbetween about 25% to about 75% (e.g., 30% to 70%) by volume of acathodic metal (e.g., platinum) co-deposited on the outer surface of thedrape to form a non-uniform mixture of the anodic and cathodic metals,wherein the coating comprises a plurality of microregions ormicrodomains of anodic metal in a matrix of cathodic metal or aplurality of microregions or microdomains of cathodic metal in a matrixof anodic metal, the microregions or microdomains forming a path ofinterconnected veins of anodic metal through the coating thickness, or apath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the outer surface of the drape). The outer surface ofthe drape (the substrate) may be prepared for the coating by using apriming coating (e.g., of titanium or other undercoating, etc.). Thecoating may be applied in a pattern (e.g., mesh pattern) which maypreserve flexibility of the substrate.

In general, any cover, clothing or draping (e.g., surgical draping) mayinclude any of the antimicrobial coatings described herein. For example,any of the apparatuses shown and described in FIGS. 26-31 may be coatedwith an antimicrobial coating as discussed above. FIG. 26 shows oneexample of a surgical (sterile) draping 2601 that may be used topreserve a surgical sterile field when using a robotic and/or mechanicalsurgical tool 2605. FIG. 27 shows another example of a cover (or drape)2701 for a surgical tool; in FIG. 27 the tool is a surgical microscope2705. An outer surface (the entire outer surface or a region thereof)may be coated with any of the antimicrobial coatings described herein.FIG. 28 illustrates another example of a cover for use in a sterileoperating field; in this example the sterile handle 2801 may be coated;alternatively or additionally, the glove 2809 may be coated or include acoating.

FIG. 29 illustrates a medical device (e.g., forceps 2905) having covers2907 that may also be coated as described herein. Either the inside,outside or both inside and outside of the covers may be coated. FIGS.30A-30B illustrate covers 3001 for medical tools (show as drills 3005)that may be sterile, and may also be coated with any of theantimicrobial coatings described herein. FIG. 31 shows an ultrasoundprove 3105 that is covered with a sterile cover 3101 that may include acoating as described above. Additional covers 3103 are shown in FIG. 31,as the single cover may be single-use.

In use, as described above, a draping or cover such as the endoscopecovers shown in FIGS. 25A-25B or the surgical drapes or covers shown inFIGS. 26, 27, 28, 29, 30A-30B and 31 may release antimicrobial ions toform an antimicrobial field when contacted with a bodily fluid. Inparticular, during a surgical procedure, contact with blood, mucus,lymph, vomit, or the like onto the coated surface(s) may initiate thegalvanic release of antimicrobial ions (e.g., silver) from the coating,as described herein. Similarly, contacting any of these coated surfacesby hand may initiate galvanic release, as a bare hand typically hassufficient surface moisture, sweat, oils, etc. to initiate galvanicrelease.

Bone Screws

In some variations, the ion-releasing implants described herein areconfigured as bone screws for treating a bone in need of treatment, suchas a broken or osteoporotic bone. The ions released may be silver, zinc,or silver and zinc. Methods for treating a tissue (including bone) arealso described herein. For example, an implant may be configured as abone screw may align, biopsy, fuse, and/or stabilize a bone. The screwmay eliminate, prevent, or reduce an infection, such as a bacterial,protozoan, or fungal infection. The treatment from the screw may providesupport to the bone and may generate therapeutic silver ions toeliminate, prevent or reduce an infection.

In general, when two metals with different redox potentials are inelectrical contact and immersed in an electrolyte, one metal maypreferentially ionize and free electrons. As the free electrons migrateto the second metal, an electrical potential, called a galvanicpotential, is created. The process requires an electron acceptor, suchas oxygen near the second metal. When the first metal is silver, ionicsilver is released. Similarly, if the first metal is zinc, ionic zinc isreleased.

The devices and systems described herein are controllable ion-releasingsystems that are configured to allow the controllable release of ions(and particularly silver and/or zinc ions) into a body with sufficientconcentration and distribution to prevent or treat infection in thetissue while also providing structural support to the region andpreventing migration of the device. Various embodiments of these devicesare described and illustrated, however the general theory of operationof all of these devices may be similar. The devices or systems may beconfigured as bone implants that treat bone and surrounding tissue, byrelease of ions such as silver ions.

As described above, FIGS. 1A-F describe a simple galvanic cell setupsuch as for use in a body. The setup is shown treating an infection, butthe same process could be applied to healthy tissue to prevent aninfection (prophylactically). The components including a first metal 2(e.g., silver), second metal 4 (e.g., platinum), and electrolytic fluid6 (e.g., blood) are shown individually in FIGS. 1A-1C and arranged in atissue in FIGS. 1D-1F. Electrolytic body fluid 6 is shown bathing orcontacting healthy tissue 10 as well as infected tissue 8. When silvermetal 2 contacts platinum metal 4 in body fluid 6, it forms a galvaniccell with a silver anode and platinum cathode. As shown in FIG. 1E,ionic silver 12 is generated and spreads through the body fluid, killingmicroorganisms and creating an infection-free zone 14 in body fluid 16in the vicinity of the anode. After treatment is complete, silver anode2 may be removed 20 leaving an infection-free body fluid 18.Alternatively, platinum cathode 4 may be removed; alternatively bothanode 2 and cathode 4 may be removed. Although the system is describedusing a silver metal anode and a platinum metal cathode, any metal witha higher redox potential than silver may be used as the cathode. Themetal may be a noble metal, such as gold, palladium or platinum. Forpurposes of illustration, the silver anode will be described as theremovable trigger for creating and stopping the galvanic response.However, either the silver or the metal with the higher redox potentialcan serve as a removable trigger (cartridge).

One embodiment of a device for controllably releasing silver is a bonestabilization device such, such as a bone screw. A bone stabilizationdevice may include a support region (e.g., an elongate rod, tube,channel, or the like) for insertion into the bone, and an insertionengagement region (e.g., a head, shoulder, coupling, etc.) for engagingwith an insertion and or removal tool. The insertion engagement regionmay be located at or near the proximal end, and may include an openingor engagement region for insertion and/or activation of a silver-release(e.g., galvanic silver release) cartridge. In some variations theengagement region includes a deployment mechanism (or contains adeployment mechanism) for activating and/or deploying silver-releasingmembers of a silver-releasing cartridge. The deployment mechanism may bereferred to as a deployment trigger. Examples of this are providedbelow.

For example, a stabilization device for controllable release of silvermay be configured as a silver-releasing bone screw. In general asilver-releasing bone screw is configured to controllably and/oractivatably release silver to prevent and/or treat infection. A bonescrew may include an elongate body (which may be threaded or otherwiseinclude one or more bone engagement surfaces) and an engagement regionat the proximal end configured as a head; one or more cartridges forgalvanic release may also be included to allow the device togalvanically release silver. For example, a bone screw according to thedisclosure may have a screw rod (elongate body) and one or morecartridges. The cartridge(s) may be configured to insert into the screwrod, and may be configured as an anti-infective cartridge or a biopsycartridge or both. A bone screw may have a platinum metal cathode and asilver metal anode. In some variations the cathode and/or the anode (orjust one or the other) may be present on the body of the bone screw; inother variations the cathode and/or anode (or both) may be present on acartridge that can be inserted and/or removed from the bone screw. Insome variations, the screw rod may be a platinum metal cathode and theanti-infective cartridge may be a silver metal anode. The cartridges mayalso include one or more anchoring, engagement, and/or stabilizationmembers that are configured to extend from the bone screw and into thebone. These members may be configured as arms, fingers, spikes, ribs,probes, struts, or the like, and may extend from the body of the bonescrew and into the tissue (including into the bone).

For example, in some variations, the screw rod is an elongated,cannulated (hollow), threaded rod. The rod may be externally threadedand/or internally threaded. Internal threads (or other guides/engagementregions) may be used to position and/or secure a cartridge within thebody. The screw rod may be sized and elongated to fit a specific type ofbone. The screw can fit any type of bone. By way of example, the screwcan be configured to fit a femur, metatarsal, tarsal, tibia, orvertebra. Threads on the outer surface of the screw rod may anchor thescrew rod into a bone or other body part. Thus, as mentioned, it may bethreaded or may include other externally-facing engagement regions. Thescrew rod may be cannulated along its entire length, or along part ofits length. The cannulated portion may create a fluid flow path. Fluid,such as oxygen carrying blood, may flow along the flow path and provideoxygen to create galvanic silver ion generation by the screw. In oneexample, the screw rod may be cannulated from a proximal end to part butnot all of the way to a distal end. The screw rod may be solid alongpart of its distal end. The solid distal end may be used to deflect aportion (e.g., anchoring, engagement, and/or stabilization members) of acartridge to be deflected from the cannulated inside to outside thescrew rod, and may also provide additional stability and/or strength tothe elongate body.

FIG. 32A shows one variation of a bone stabilization implant fordelivering an antibiotic (e.g., silver) in a controllable manner to aregion of bone and/or surrounding tissue. In this example the bonestabilization device is configured as a bone anchor screw including anelongated, cannulated screw rod 22 region. Screw rod 22 has elongatedbody 26 and threads 24. Threads 24 are configured to penetrate a part ofa bone and/or to hold the screw in place in a bone or body region.

The screw may have a screw head 28 at a proximal end with one or morefeatures to aid in holding, placing and/or removing the screw rod andfor inserting and/or activating the cartridge. FIG. 32A shows oneexample of a screw head configured as a grippable screw head 28. Thescrew head may engage an insertion device and/or removal device. In somevariations the screw may have a shaped head, such as hexagonal head 56shown in FIGS. 35 and 36 that can be gripped by a wrench or othergripping tool. The feature may also be used to hold the rod screw inplace while inserting or removing a cartridge or performing othermanipulations.

The inside of the screw rod may have connection means for connectingwith or attaching an insertion tool. In one example, the screw rod mayhave threads inside the screw rod (internal threads). The internalthreads may be along part or maybe along the entire internal length ofthe screw rod.

The bone screw example shown in FIG. 32A includes a screw rod with achannel or opening 30. The screw rod may have just one channel oropening or may have more than one channel or opening. The channels oropenings may be sized and shaped to allow at least part of a biopsycartridge and/or anti-infective cartridge to move outside cannulatedscrew rod.

The shape and pitch of the screw rod external threads may be angled orshaped to aid or direct cartridge placement. FIG. 32A shows screw rodexternal threads 24 that may aid placement of a cartridge. Thecannulated screw rod may have a port or ports (e.g., an opening) aroundthe channel that is configured to guide a portion of a biopsy elementand/or anti-migration/anti-infection element of a cartridge from insidethe cannulated screw rod to outside.

The screw rod may be made of any biocompatible material that issufficiently strong to be inserted into a body (bone) region. Forexample, the screw may be made, at least in part, of a steel (e.g.,stainless steel), or other material. In some variations, the screw rodis made of platinum, titanium, or stainless steel material that iscoated with platinum, palladium or gold. In particular, the screw rodmay be coated with a material or materials that are able to create agalvanic response with silver. The coating may be over the entiresurface of the screw rod or may be over part of the surface. The coatingmay be in the form of bands. The coating material may be a noble metalthat has a greater galvanic potential than silver in a body. The noblemetal may be gold, palladium, or platinum.

The rod screw may have features to increase its surface area. Inparticular, in variations in which the anode or, more likely, thecathode is located on the surface of the screw body, the portion of thescrew body forming the cathode may have a relatively large surface area(particularly as compared to the opposite redox partner, e.g., anode). Alarger surface area may create a higher galvanic current for generatingtherapeutic silver ions. The rod screw may comprise foamed metal on itsinside surface, outside surface, or both surfaces.

In some variations the screw or rod configured as a stabilization devicewith controllable silver release may include on ore more features toincrease opportunities for contact with body fluid. Increased contactmay allow a stronger, faster, or longer galvanic response. FIGS. 35 and36 show examples of rod screws 50, 51 with openings 60 along body 54 inaddition to openings near threads 51. These openings may allow increasedfluid flow, such as blood flow, around and through the rod screw. Someor all of these opening may also be configured to allow exit of one ormore members (e.g., arms, struts, etc.) from a cartridge.

Any of the devices described herein may include or be configured for usewith one or more cartridges. In general, a cartridge is aremovable/replaceable element that may be inserted into or alongside ofthese support and antimicrobial devices (e.g., screws). As mentionedabove, the cartridge may include one or more members that are configuredto be extended out of the device and into the surrounding tissue. Thesemembers may be referred to and configured as struts, probes, legs, arms,hooks, wires, coils, fingers, spikes, ribs, or the like; in general theyare elongate members that may be inserted into the patient's tissue andextend away from the body of the device. The members may therefore beconfigured to help secure the device within the tissue. For example, themembers may enhance the mechanical attributes of the device, includingpreventing the device from pulling out of the tissue.

A cartridge may be referred to as an anti-infection cartridge if it isconfigured to aid in the release of silver ions from the device. Forexample the cartridge may include one or more members having silver(e.g., anode) regions or configured so that an entire member is silverreleasing. In some variations the cartridge may also be referred to as abiopsy cartridge that is configured to remove tissue (e.g., bone, softtissue, etc.) for testing. In some variations the cartridge may beconfigured as both an anti-infection and a biopsy cartridge.

An anti-infection cartridge may include a cathode. For example, thecartridge may include a plurality of arms, some of which are formed of ametal such as platinum that can react with the silver anode to releasesilver. As mentioned, in some variations the body of the implant devicemay include all or portion of the cathode.

In the examples illustrated herein the treatment cartridges are shown asseparate elements that may be inserted into the devices. For example, acartridge may be inserted into the device after the device (e.g., screwbody) has been implanted into the bone. Cartridges may be replaced orrecharged (e.g., replacing a portion of a cartridge such as asilver-containing member) without removing the entire device from thepatient.

In some variations the cartridge is integral with (or part of) theimplant device (e.g., screw).

The anti-infection cartridge may serve other functions in addition to orinstead of being anti-infective. For example, it may be configured toprevent device migration. In some variations, including thoseillustrated below, a plurality of member extend from the device body(e.g., the body of the bone screw) and push into the tissue to helpanchor the device. Thus, the cartridge member(s) may be configured topenetrate tissue, including bone. In some variations the members arerigid/stiff member and may also include tissue-penetrating distalregions. For example, one or more members may be stainless steel, nickeltitanium, or the like (which may be coated with silver in somevariations).

Thus, an anti-infection cartridge may comprise silver or a silvercoating, plating, or the like. The anti-infective cartridge may beconfigured to be easily inserted and/or easily removed from thecannulated device (e.g., screw). In some variations, the cartridge has aholding end and a probe end. The holding end may be configured to bereadily held, gripped or grabbed by a hand or by a device. By way ofexample, the holding end may be a loop, V shape or U shape, or mayinclude a grip region. The probe end may be configured to contact a bodypart or a body solution. In general, the probe end is configured as oneor more members that extend from the implant device when it isimplanted. For example, the probe end may be configured as one or moremembers that extend from the screw rod. This may allow the silver ionsto be directed to a particular body region, or it may create a largerregion of therapeutic silver ions, or it may allow the cartridge tobetter contact or grip or hold a body surface.

FIG. 32B shows one example of an anti-infection cartridge 32; theproximal end may be referred to as the holding end 37, which can begripped by a hand or tool. The distal end of the cartridge in thisexample has two probe ends that can extend out of the body of the screwdevice. In FIG. 32B, the ends 33, 35 of the two members of the cartridge32 can be inserted into a screw rod portion of a screw of rod forimplantation into the body (bone). In this example the body of the screwrod includes a cathode 22 along the outer surface of the screw; theanodes on the elongate members of the cartridge contact the cathodalsurface of the screw when they are extended from the implant. Each probeof the cartridge may have multiple probe ends. The probe ends may beconfigured to contact a portion of the bone or other tissue to hold thecartridge and bone screw in place. The probe ends may be positioned(spread apart) to create a larger area of effective silver ion area.

The anti-infective cartridge may be placed in contact with a screw rodto generate a galvanic screw in variations having the anode(s) on thecartridge and the cathode on the body of the implant (e.g., screw). Forexample, FIGS. 33 and 34 illustrate placement of an anti-infectivecartridge 32 such as the one shown in 32B in contact with a screw bodysuch as the one shown in FIG. 32A. The cartridge arms are extended inFIG. 34. In this example the cartridge includes two members, each formedof the twisted wires shown. In one variation the wires are both silverwires; alternatively one wire may be silver and the other wise stainlesssteel or the like, adding column strength for insertion, such as may behelpful for use in bone. For example, in FIG. 33 the probe ends of thecartridge pass through the center of cannulated screw rod 26 and may beheld there until they are deployed into the tissue. When they aredeployed (e.g., after implanting the device into the bone) the implantmay include deflection/guide regions that steer the members out of theimplant and into the tissue. For example, the threads 24 of the screwbody in FIGS. 33 and 34 may receive or guide the probe ends as theyexit. As the cartridge 32 is advanced, probe ends 33 and 35 exit throughopenings 30 in the screw body. As mentioned, extending the probes intothe tissue may provide mechanical resistance to inhibit unwanted removalor movement of the probe and/or screw. In some variations the distal endof the probes may be sharp or otherwise tissue penetrating.

A biopsy cartridge may share many similarities with an antimicrobialcartridge as described above. For example, the biopsy cartridge mayinclude one or a plurality of members configured to extend from the bodyof the implant device (e.g., arms, struts, etc.). In some variations thedistal ends of these members may include one or more tissue captureelements such as a cup, hook, scraper, basket, needle, etc. A cartridge(including a biopsy cartridge) may also include an attachment site orcoupling for a proximal handle (e.g., a threaded region or the like). Insome variations a biopsy cartridge may be paired with an antimicrobialcartridge and the two may be exchanged from the same implant device. Forexample, the implant device (e.g., screw body) may be inserted and anantimicrobial cartridge and a biopsy cartridge may be alternatelyinserted to sample, then treat, then sample (in any appropriate order)the bone. In some variations the members of the biopsy device are longer(or are capable of extending to a longer length) than the members of theantimicrobial cartridge, to sample bone regions beyond the sites inwhich the members of the antimicrobial cartridge resided. In somevariations the insertion length of the cartridge member(s) is variable,and may be selected or modified by a user when inserting or deployingthe cartridge.

FIGS. 37A-C, 38A, 38B, 39A, and 39B describe another embodiment of agalvanic screw system for treating or preventing infection. Thesesystems typically include a support device body (e.g., screw or rodbody) and one or more cartridges, as described above. A screw system mayhave a collapsed or un-deployed configuration and an expanded ordeployed configuration. In some variations, toggling between thedeployed and un-deployed configurations controls the galvanic potential.For example, in some variations, extending the members of the cartridgeincluding the silver anode may start the galvanic current by placing theanode in electrical contact with the cathode.

Additionally, because of the relatively streamlined initial size/shape,the un-deployed configuration of the system/device can readily beinserted into a bone in a less invasive way and expanded into thedeployed configuration once it is place, limiting any damage or traumato the tissue.

When the screw is in an un-deployed configuration, the galvanicpotential is essentially off. When the screw is in an expanded position,the cathode and anode are in electrical contact with each other and thegalvanic potential is on. As the amount of silver in the implant may belimiting, it may be useful to keep a galvanic potential turned off whenit is not needed and conserve the potential for future use. The implantmay be kept in the collapsed (off) or partially collapsed (off)configuration for any reason. For example, the implant may be configuredto be switched “off” (stopping the galvanic release of silver) if thereis no evidence of a current infection, but a future infection may beexpected, as might be the case in a joint implant. Joint implants havebeen reported to develop infections months or years after beingimplanted. By implanting one of the devices as described herein forcontrollably delivering silver, but leaving galvanic potential “off”,the implant may conserve the silver for use if and when an infectiondevelops.

Thus the devices and systems described herein may be configured to allowthe anode to be electrically isolated from the cathode (switching “off”the delivery of silver by the device) until it is desired to becontrollably released. For example, the electrical connection betweenthe anode and the cathode may depend upon the extent to which acartridge having members is extended from the body of the device. Insome variations, a conductive bridge (e.g., switch) between the anodeand cathode may be moveable into and out of position to turn “on” or“off” the galvanic reaction. This is described below in reference toFIGS. 42A-42B. In other variations a switch is not necessary, as theanode and cathode may be place in electrical connection by fully orpartially deploying the cartridge (e.g., the members of the cartridge);in the un-deployed configuration the anode may be electrically isolatedfrom the cathode.

In some variations, the activation of the silver release from theimplant may depend upon controlling exposure of the anode and/or cathode(which may be in electrical contact) to an electrolytic solution. Forexample, the cathode and/or anode may be retracted into thefluid-impermeable body of the device until it is desired to releasesilver ions.

Note that the controllable release of silver as described herein mayalso refer to the controllable distribution of silver released into thebody. In some variations the pattern of distribution of the silver inthe body may be determined in part by the arrangement of the member inthe deployed configuration. As the members are expanded away from thebody of the device (e.g., the screw body or rod body) a much largerpattern (e.g., “cloud”) of silver ions having antimicrobial effects at alarger concentration could be achieved than in comparison to an implantor device having only a coating of silver, even actively releasedsilver. In some variations, the implant may be configured to allowcontrol of the extent of the deployment of the members; for example,extending the device only partially from the body of the device asillustrated in FIGS. 37A-38B.

FIGS. 37A-37C show a device for controllably delivering silver ions thatis configured as a screw 60; in this example, the screw has beeninserted in a bone 62 having an infected region 66. The implant isbathed in a body fluid 64. FIGS. 37B-37C show views along line 32B ofFIG. 37A, showing the internal cannulated passage through the elongatescrew body 76. The implant is anchored in cancellous bone 82 initiallyby threaded portion 78, with the rest of implant body 76 in this examplepositioned within the cortical bone 80. In this example, six membersformed as anodes (silver containing regions) are configured as ribboncoils 84 that can be rotated to deploy them out of openings 74 on thebody of the screw. The ribbon coil 84 is held inside rod screw 60 nearslots/openings 74 between threads 78. These deployable members are partof the loaded (e.g., preloaded) antimicrobial cartridge 72. Thecartridge may be rotated when positioned within the screw body to deploythe members from the screw and into the tissue. The device also includesa screw head 68 at the proximal end and a deployment trigger 72 which isconfigured as a trigger head 72 in this example. Screw head 68 has slots70 which can be used to insert (e.g., screw in) the screw into the bone,and/or to hold screw body when manipulating trigger head 72 or can beused to otherwise insert, remove, or manipulated the screw.

In the exemplary device shown in FIGS. 37A-37C, the silver releasingmembers of the cartridge may be deployed by rotating the trigger.Referring to FIG. 37C, the trigger head 72 may be rotated (e.g.counterclockwise), causing ribbon coils 84 to move into position underslots 84 and to unfurl to form probes 88 that extend from the elongatebody of the screw. As the members extend from the body, silver on themembers (forming a cathode) is placed in electrical contact with thecathode formed on the outer surface of the screw body 76; thus thegalvanic potential is on, and silver may be released into the tissuethat is bathed in the electrolyte solution (e.g., blood). Thus, members88 include a silver-releasing anode that is electrically communicatingwith the platinum cathode on the screw body 76. In this manner, silverions may be released in a region surrounding the implanted screw body,and silver ions 90 may clear infection 66 to create a clear zone 88 intissue around the implant.

In the example shown in FIGS. 37A-37C the device for antimicrobialsilver release may include a cartridge having the coiled arms that canbe extended from the body. In some variations, the cartridge is integralwith the body of the device. For example, in FIGS. 37A-37C the cartridgecomprises the inner rod member connected proximally to the trigger; thecartridge includes the coiled member wrapped around the inner rodmember. The inner rod member may be rotated within the body. In somevariation the inner rod member is permanently fixed within the body ofthe device. In some variations the inner member forming the rotatablemay be removable from the body of the device. Thus, the inner member maybe recharged and/or replaced while leaving the screw within thepatient's bone.

FIGS. 38A and 38B show another variation of a device configured as ascrew similar to the one in FIG. 37 A-C with tilted slots 104 betweenthreads 102 on rod region 100 in order to bias ribbon coil 106 to exitthe body at an angle. In general, the device body may include one ormore guides, channels, or the like for directing the members (“ribboncoil 106”) from the cartridge (e.g., inner rod) away from the body ofthe device at an angle or along a pathway. For example, in somevariations the device's threads near the distal end of the device may beused to deflect and direct the extending members and thereby control theextent and location of antimicrobial “cloud” surrounding the implant asthe ions are released.

FIGS. 39A and 39B show a top view of another variation of a deviceconfigured as a screw similar to the ones shown in FIGS. 37A-38B. Thisvariation includes more members (probes 114), which may be distributedmore tightly or specifically around the device. In this example, thetrigger head 108 is shown inside rod screw head 110. Slots 112 on screwhead 110 can be used to hold the device head 110 relative to triggerhead 108 to manipulate the trigger relative to the screw, or screwrelative to the bone. In another example, the interior surface and/orouter surface of the screw head 110 may be shaped to engage and/or begrippable by a cannula or other insertion/removal device during screwinsertion, removal, or repositioning. The internal shape of the proximalend of the device may be any shape that allows an insertion/removaldevice to grip the internal surface and to move (e.g. rotate) the screw.The internal shape may be, for example, hexagonal, square, triangular,or threaded. The internal shaping may be only in the head or may extendthrough part or the entire length of the screw. Being able to grip morethan just the head of the screw may better distribute force applied(e.g. torque) to move the screw (e.g., during insertion, removal orrepositioning) and thereby prevent the screw from breaking, stripping,or otherwise being damaged. When the multiple arms (probes, coils, etc.)are extended into the tissue (e.g., bone) from within the bone implantdevice, these member may (in addition to releasing silver) providedadditional anchoring to the implanted device. For example, theextended/deployed arms provide mechanical resistance to inhibit unwantedremoval or movement of the device.

In general, the cartridges described herein can be assembled from anymaterials that will allow them to be deployed from an implanted deviceand release silver ions and/or remove (biopsy) tissue. For example,FIGS. 40A-40D show a device, configured as a screw, and a cartridge,formed from a memory shaped ribbon. FIG. 40A shows the shape of theribbon 124 and the screw device 120. In this example, ribbon 124collapses to assume collapsed configuration 126 as it's inserted intohousing 120. Collapsed ribbon 126 is pushed or turned into position sothat probes 125 can expand through slots 122.

Bones that have been subject to mechanical trauma, infection or otherforms of insult may be prone to further damage during insertion of abone screw. Inserting a bone screw with mechanical properties that arecloser to those of bone may reduce or prevent further trauma. FIGS.41A-C show a bone screw in which the mechanical properties of the bonescrew are relatively similar to the mechanical properties of the bone,but which is still able to generate therapeutic silver ions. In thisexample the elongate body of the device 130 includes a threaded distalend region and a proximal spring region. The device is shown in FIG. 41Band the cartridge for use with the device is shown in FIG. 41A. FIG. 41Bshows a platinum (or platinum coated) screw with a threaded distal end134 and a proximal spring end 137. Screw end 134 may be inserted into abone by turning hex 136 with a driver. In any of the variationsdescribed herein, an initial (e.g. pilot) passage into the bone may bedrilled or otherwise formed before implanting the device. Stop 138 maybe used to prevent the screw from being inserted too far into the bone.Once rod screw 130 is in place, a cartridge comprising, in this example,a silver screw or spring 132 as shown in FIG. 41A can be screwed intorod screw 130. The result is the two springs coiled together 144 asshown in FIG. 41C. The contact between the platinum or platinum coatedcoiled region of the device body 137 and the coiled and silver or silvercoated region of the cartridge 132 is sufficient that when in thepresence of an electrolytic solution, silver ions will be released fromthe implant.

Another example of a trigger or switch for controlling the release ofsilver ions (e.g., for creating a device having a controllable on/offapplication of silver ions) uses a magnet as shown in FIGS. 42A-42B. Inthis example a control magnet is shown outside the body, external toskin 155 while screw 152 is shown screwed into cortical 154 andcancellous 156 regions of bone 152 in the body. Application of externalmagnetic force (e.g., magnet 158) repels or attracts a correspondingmagnetic region within the implant 160, causing it to move the cartridge162 into or out of position to expand probes 162 out of screw 150 orretract them into the screw. For example, in FIG. 42B, application ofexternal magnet 158 attracts the internal cartridge implanted with thescrew, causing it to move the cartridge 164 towards it in a contractedposition. Lateral movement of the cartridge results in extending orretracting the members of the cartridge into and out of the screw body,thereby turning on or off the release of silver ions from the screw.

In use, several bone screws can be used together for larger bones orbones otherwise requiring more support or treatment as shown in FIGS.43A-43B. For example, FIG. 43A shows a series of bone screws 190inserted through a bone plate 190 that is adjacent to a cortical bone194 and treating large infection 188 near fracture 186 in femur 180.Each screw has multiple silver-releasing members 194 extending intocancellous bone 184 to create a large silver therapeutic area. FIG. 43Bshows an alternative embodiment in which some silver/silver coated rodscrews 196 are alternating with platinum plated or noble metal rodscrews 198.

The bone screw, methods, and systems described herein may be used withany type of bone, including long bones. FIG. 44 shows a bone screw 202configured to release silver ions similar to those in FIGS. 32A-33Babove, inserted into a portion of a jaw. Therapeutic silver ions 206 arereleased from members 206. The screw may be configured to attach atooth, crown or other dental appliance. FIG. 45 shows bone screws and aplate attached to a mandible such as might be used in a reconstructivesurgery to prevent or treat infections. FIG. 46 shows bone screws andplates used in various bones of the jaw, face, and skull 220.

In some variations, the anti-infective cartridge includes a lock on thecannulated screw and/or rod to hold the cartridge in place relative tothe elongate body of the device. Thus, the cartridge may be locked in aconfiguration (e.g., deployed, un-deployed, etc.) within the body of thedevice. The lock may be releasable; for example, the lock may include alatch.

As mentioned above, the cartridge may be configured as a biopsy (e.g.,assay) cartridge, which may be used instead of, or in addition to ananti-infection cartridge; in some variations the cartridge is acombination of both anti-infective and biopsy. In general a biopsycartridge may be coupled to the body of the device and used to withdrawa sample of tissue from around where the implant has been insertedwithout having to remove the device (“implant”) from the body. Forexample, in some variations, the biopsy cartridge is inserted throughthe cannulated elongate body of the device (e.g., of a screw body) andone or more members of the cartridge extends from the elongate body,similar to the silver-releasing members extending from thesilver-release cartridges described above, to make contact with aportion of the body to be assayed, to obtain a biopsy (assay) sample,and to be removed. The biopsy sample can be assayed in any way afterbeing removed from the patient. Thus, the biopsy cartridge may have anexpanded (deployed) form and a collapsed (un-deployed) form. The biopsycartridge may be expanded before obtaining a biopsy sample and may becollapsed after obtaining a biopsy sample. Any of the structuresdescribed in the disclosure for the anti-infective cartridge and any ofthe methods described for inserting, using, or removing the cartridgemay also or instead be used for the biopsy cartridge.

Although many of the examples described above are configured so that thedevice body is configured as the cathode (e.g., comprising a platinummaterial) while the extendable members from the cartridge are the anodematerial (e.g., silver or silver coated), in some variations thisconfiguration may be reversed. For example, the device body (e.g., thescrew body, rod body, etc.) may be silver or silver coated and theanti-infective cartridge may configured as the cathode, comprising anoble metal such as gold, palladium or platinum to create a galvanicresponse in the body and release silver ions.

In general, the devices may be inserted or implanted into the body,e.g., into the bone, either before during or after engaging a cartridge,including an anti-infective and/or biopsy cartridge. For example, adevice configured as a silver-delivering screw may be inserted into abone, loaded with an anti-infective cartridge or biopsy cartridge byinserting the cartridge through the elongate body (e.g., from theproximal end of the screw rod). A biopsy cartridge may be inserted andremoved before, after, or instead of insertion of an anti-infectivecartridge. In one example, a biopsy cartridge is inserted through thedevice body, takes a biopsy sample, and is removed before anti-infectivecartridge is inserted. In another example, an anti-infective cartridgemay be inserted, left in the body for a period of time to createtherapeutic silver ions, and removed before a biopsy cartridge is usedto remove a biopsy sample to determine an effectiveness ofanti-infective treatment. In another example, an anti-infectivecartridge may be inserted, left in the body for a period of time tocreate therapeutic silver ions, and removed before a biopsy cartridge isused to remove a biopsy sample to determine an effectiveness ofanti-infective treatment.

In another example, a first anti-infective cartridge is placed throughthe device implanted in the body and one or more anti-infectivecartridges are additionally placed in the device body, without removingthe first anti-infective cartridge. The cartridges may degrade (e.g.,corrode as the silver is release) or simply avoiding by precedingcartridges.

In another example, a first anti-infective cartridge may be removed froman implanted device in a body and a second anti-infective cartridgeinserted. This process may be repeated. This may be done, for example,if there is insufficient therapeutic silver remaining on a firstcartridge. The screw rod and any of the cartridges may be left in thebody for any length of time. They may be left in for less than thirtydays (e.g. a few days, a week, or several weeks) or they may be left infor more than thirty days. In one example, the screws may be left inpermanently.

EXAMPLES

Any of the exemplary ion-releasing devices described above may be usedto treat (or prophylactically treat or prevent) infection and/or supporttissue. Exemplary methods of use are illustrated below. These examplesare intended only to illustrate how one such implant may be operated,and is not intended to be limiting or limited to any specific variation.

In general, the implants for controllably providing antimicrobialtreatment and support may be used to treat any tissues of the body, butparticularly bones, including the long bones (such as the femur, tibia,radius, ulna, fibula, metacarpal, metatarsal, phalanges, etc.), thespine, and the skull. In some variations the device is configured forinsertion into the medullary canal of a lower extremity bone, such as afemur, tibia, tarsal or metatarsal, for the alignment, stabilization,fixation and bone biopsy of various types of fractures or deformitiescaused by trauma, infection or disease. Examples of such fracturesinclude: traumatic fractures, re-fractures, non-union, reconstruction,malunion, malalignment, pathological fractures due to infection ordisease and impending pathological fractures. The ion controlled releasesystems may have silver and/or zinc coated struts that expand out fromthe body of the device to form a three-dimensional array to stabilize,minimize device migration and form an antimicrobial barrier to reducemicrobial colonization on the external surfaces of the device.

An implant that controllably provides antimicrobial treatment, such as abone screw for controllably releasing silver ions, may be used to repaira bone fracture. The bone may first be prepared to receive the device.Pre-existing deformities may be corrected prior to the preparation andinsertion of a device such as those described above configured as acontrollable silver-ion releasing bone screw (e.g., intramedullary or IMscrew). The anatomy of the deformity, surgeon preference, and patientpositioning may determine the appropriate approach chosen for jointpreparation and alignment.

For example, a bone implant that controllably provides antimicrobialtreatment may be use used to repair a broken ankle. Upon properlyaligning and preparing all the joint surfaces, the ankle may bepositioned for arthrodesis. The ankle may be medizlized by thoroughdebridement of medial gutter facilitates positioning in the center ofthe calcaneus, talus and tibia. The ankle may then be placed in neutraldorsiflexion and symmetric external rotation of the contralateral ankle.This position may be maintained throughout the procedure, and may befacilitated by provisionally placing a wire on the periphery of theankle joint.

Under fluoroscopic control, a 2-3 cm longitudinal incision may be madejust above the location for the bone insertion point. After the incisionis made, dissection may be continued down to the surface of the targetbone by bluntly dissecting through the soft tissues, noting the locationof neurovascular bundles. Thereafter, the device (e.g., a controlledsilver ion releasing implant or bone screw) may be inserted. Anintroducing cannula can then be selected and placed against the boneinsertion point. The hand reamer may then be used to carefully reamthrough the cortical bone into the intramedullary canal. The cannula isnot advanced into the bone. The position of the hand reamer underfluoroscopy may be monitored under floro periodically. The hand reamercan be removed from the cannula.

Thereafter, the surgeon may select the proper size implant device IMscrew rod that is pre-mounted on trocar. Advance the screw rod into thebone by turning clockwise. Periodically stop and check under fluoroscopythe position of the screw rod with respect to the opposite corticalside.

Finally, the trocar device may be removed from the inside of thecannulated screw rod by turning clockwise.

In some variations, the bone implant that controllably providesantimicrobial treatment may also be used to take a biopsy before, duringor after insertion of the implant. The implant may be inserted into thebone as discussed above, and a bone biopsy cartridge may be insertedthrough the internal cannula of the implanted device. The proximal endof the cartridge may be grasped direction of coupled to a handle formanipulation by a surgeon. The distal end of the biopsy cartridge mayinclude one or a plurality of cupped wires that can be extended from theimplant body and used to sample the tissue. For example, one or morecupped wires may be deployed through the ports of the body of ascrew-type implant. This may be met with some resistance from thecancellous bone. Extension of the biopsy cup wires can be confirmed byfluoroscopy. After deployment of the wires, the proximal end of thecartridge may be pulled back and the wires retracted, capturingcancellous bone for biopsy in the cups of the cartridge. The cartridgemay be removed from the rest of the implant, and placed in a sealed,labeled laboratory infectious disease container for further processing.

In general, the antimicrobial cartridges described herein may beinserted and/or deployed as mentioned above. For example, a cartridgemay be removed from a foil sterile package. The cartridge may be storedin a sealed package with an indicator to indicate if the packageintegrity has been compromised. For example, the package may include anindicating desiccant (e.g., pouch) that visually indicated, e.g., by aline that changes red, if the packaging has been breached and exposed tohumidity.

The cartridge may be inserted into the device housing, e.g., the centralbore or cannula within the elongate cannulated body. In some variationsthe cartridge is pre-loaded into the body of the device. The cartridge,and particularly the elongate members of the cartridge at the distalend, may be inspected and/or aligned with the cannulated body so thatthey may be extended through openings in the body to extend from thebody when implanted. The cannulated body may include a guide, channel,keying, etc. to aid in aligning and inserting the cartridge into thebody. In some variations the inner surface of the cannulated body iskeyed (including threaded) to guide the insertion of the cartridge; anouter surface of the cartridge may mate with and engage the innersurface of the cannulated body.

An insertion tool (e.g., handle) may be used to help insert thecartridge into the elongate cannulated body of the implant. For example,the insertion/removal tool may be an elongate rod having a coupling andor mount its distal end region to connect to a cartridge. In somevariations the insertion/removal tool may include an inner body regionfor holding the cartridge in the collapsed/un-deployed configurationafter or before it has been connected/removed from the implant body. Forexample, the cartridge may be “collapsed” by the action of the insertiontool. The distal end of the insertion tool may include a chamber,cannula, etc. for holding the cartridge in a collapsed configuration;the cartridge may be pushed out of or otherwise extended from the handleinto the implant, allowing the members of the cartridge to extendthrough the body of the device and into the tissue.

Thus, the distal ends of the members may be extended away from the bodyof the implant and into the patient tissue so that the members willdeploy through the ports of the device. In some variations thisdeployment is guided by the implant body which deflects and/or guidesthe members as they are extended. For example, the threads of an implantconfigured as a bone screw may be arranged to deflect the membersoutward and into the tissue. After insertion and/or deployment of thecartridge in variations requiring it, any inserter tools may bewithdrawn and proper positioning may be confirmed using fluoroscopy.

Thereafter, the stability and operation of the device may be verified,and the surgical access/insertion site may be closed, at least for someamount of time. In some variations the cartridge may bereplaced/recharged into the same implant over the course of weeks,months or years.

Once the implant has exceeded its useful life, it may be removed fromthe patient or left in place. In some variations it may be desirable toleave the implant in place so that it can continue to provide structuralsupport. This may be true even of the cartridges, as any extendedmembers that have been extended into the tissue may continue to providestructural support even if the source of silver ions has been exhausted.

The cartridges may be removed in many cases by reversing the insertionprocess just described. In some variations the cartridge may remainwithin the bone for approximately 30 days or more. The implant may beremoved with a removal device configured to couple to the proximal endof the cartridge and/or to release the cartridge from the device body.

In some variations a retrieval kit may be used. For example, a retrievalkit may include a removal device (configured similarly to an inserter).To remove the device, surgical aseptic technique (under fluoroscopy) maybe used to make a small incision directly above the site of the previoussurgery. The removal device (cartridge retrieval device) may be insertedand attached to the proximal end to the outer housing to stabilize it.In some variations the retrieval device has an elongated body with adistal end that is adapted to couple or abut (e.g., adjacently contact)the implant device body and a second region that is configured to couplewith the proximal end of the cartridge. For example, the retrievalmember may include a central shaft having a distal end adapted to couple(e.g., screw onto) the proximal end of the cartridge and an outercannula surrounding the central shaft that is configured to couple tothe proximal end of the implant device. In some variations the retrievaldevice includes a proximal forceps that may be used to couple to theinner cartridge. Such configurations (or similar configurations) mayallow sufficient leverage to remove the extended members and withdrawthe cartridge form the implant and the body, retracting the membersthrough the outer housing ports and collapsing them for removal.

After removal, the cartridge may be disposed of or used to providebiopsy material. The surgical site may be examined directly and byfluoroscopy. If it appears that the site (and implant) would benefitfrom additional anti-migration or anti-infection elements, a newcartridge may be re-deployed for another treatment period (e.g., 30days) and the process repeated.

Although the illustrations described above illustrated primarilythreaded screw variations, it should be apparent that non-treadedvariations and non-screw variations are contemplated. For example, thedevices for controllable release of silver ions described herein may beconfigured as nails, rods or the like.

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements, these features/elements should not be limitedby these terms, unless the context indicates otherwise. These terms maybe used to distinguish one feature/element from another feature/element.Thus, a first feature/element discussed below could be termed a secondfeature/element, and similarly, a second feature/element discussed belowcould be termed a first feature/element without departing from theteachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/− 0.1% of the stated value (or range of values), +/−1% of the stated value (or range of values), +/− 2% of the stated value(or range of values), +/− 5% of the stated value (or range of values),+/− 10% of the stated value (or range of values), etc. Any numericalrange recited herein is intended to include all sub-ranges subsumedtherein.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. An apparatus that galvanically releasesantimicrobial ions, the apparatus comprising: a cartridge; and a coatingon the cartridge, the coating comprising a mixture of an anodic metaland a cathodic metal co-deposited on the cartridge, wherein the coatingcomprises a plurality of microregions or microdomains of anodic metal ina matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming interconnected veins of anodicmetal through the coating thickness, or interconnected veins of cathodicmetal through the coating thickness, wherein the interconnected veinsextend from an outer surface of the coating through the coating to anopposite side of the coating; wherein the anodic metal is galvanicallyreleased as antimicrobial ions when the apparatus is exposed to a bodilyfluid.
 2. The apparatus of claim 1, wherein the coating form a patternon the cartridge.
 3. The apparatus of claim 1, wherein the coating formsone or more of: a sinusoidal pattern, cross-hatched pattern, a meshpattern, a web pattern, and a zig-zag pattern.
 4. The apparatus of claim1, wherein less than 30% of the anodic metal is fully encapsulatedwithin the matrix of cathodic metal and connects through a microregionor microdomain of anodic metal to the outer surface of the coating. 5.The apparatus of claim 1, wherein less than 20% of the anodic metal isfully encapsulated within the matrix of cathodic metal and connectsthrough a microregion or microdomain of anodic metal to the outersurface of the coating.
 6. The apparatus of claim 1, wherein the anodicmetal comprises both zinc and silver.
 7. The apparatus of claim 1,wherein the anodic metal comprises silver, zinc or copper.
 8. Theapparatus of claim 1, wherein the cathodic metal comprises one or moreof: palladium, platinum, and gold.
 9. The apparatus of claim 1, whereinthe cathodic metal comprises one or more of: palladium, platinum, gold,molybdenum, titanium, iridium, osmium, rhodium, manganese, niobium andrhenium.
 10. The apparatus of claim 1, wherein the coating comprises theanodic metal and the cathodic metal that have been vapor-deposited sothat the anodic metal is not encapsulated by the cathodic metal.
 11. Theapparatus of claim 1, wherein the coating is fractured.
 12. A method ofdelivering silver, zinc, or silver and zinc ions from an implant toprevent or treat infection, the method comprising: engaging the implantwith a removable cartridge having a coating comprising a mixture of ananodic metal and a cathodic metal co-deposited on the cartridge, whereinthe coating comprises a plurality of microregions or microdomains ofanodic metal in a matrix of cathodic metal or a plurality ofmicroregions or microdomains of cathodic metal in a matrix of anodicmetal, the microregions or microdomains forming interconnected veins ofanodic metal through the coating thickness, or interconnected veins ofcathodic metal through the coating thickness, wherein the interconnectedveins extend from an outer surface of the coating through the coating toan opposite side of the coating; and activating a control to initiatethe galvanic release of silver, zinc or silver and zinc from thecartridge.
 13. The method of claim 12, wherein engaging the implantcomprises coupling the removable cartridge with the implant when theimplant is already inserted into a patient.
 14. The method of claim 12,further comprising placing at least a portion of the cartridge incommunication with a source of oxygen comprising greater than 7×10⁻⁵mol/L of oxygen.
 15. The method of claim 12, further comprisinginserting the implant into a patient's body.
 16. The method of claim 12,further comprising inserting the implant into a bone.
 17. The method ofclaim 12, wherein activating comprises extending the cartridge from achamber within the implant into a patient tissue.
 18. The method ofclaim 12, wherein engaging the implant comprises extending a pluralityof ion release members from the cartridge out of openings in the implantbody.